Oral Bioavailability and Drug Delivery - 2023 - Hu - Drug Drug Interactions and Drug Dietary Chemical Interactions

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26
Drug–Drug Interactions and Drug–Dietary Chemical Interactions

Mengbi Yang, Yuanfeng Lyu, and Zhong Zuo
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR
26.1 Introduction 26.2 Drug–Drug Interactions (DDIs)

Nowadays, patients frequently use more than one Major pharmacokinetics-based DDIs in human is
medication at a time. The incidence of potential summarized in Table 26.1, in which the specific mecha-
drug–drug interactions (DDIs) could be as high as nism of interactions, victim drug, and perpetrator drug
80% based on the specific clinical settings and the together with their pharmacokinetics outcomes are
number of drugs prescribed [1]. DDIs can be mainly listed. The major pharmacokinetics-based DDI hap-
classified into pharmacokinetics-based interactions pened during the oral absorption, hepatic metabolism
and pharmacodynamics-based interactions, leading and tissue distribution, and kidney elimination pro-
to either favorable or toxic effects. Among our recent cesses. The related mechanisms include formation
literature search of clinically evidenced DDIs reported of insoluble complex in gastrointestinaal (GI) tract,
since 2007, about 113 clinical studies are found to be alteration in gastric pH, GI motility, and activity of
related to pharmacodynamics-based DDIs, while 36 transporters and metabolic enzymes, which are further
clinical studies are on pharmacokinetics-based DDIs. elaborated as follows:
Most of the pharmacodynamics-based DDIs are related
to disease conditions, which require complex combina- 26.2.1 Interactions Involved in Oral Absorption
tion therapies, including cancers, AIDS, and series of of Small Molecules
psychological disorders, and their clinical outcomes are
Since GI tract is the primary absorption site for orally
usually additive effects that could be predicted based
administrated drugs, its physiological properties such as
on the mechanism of actions for the drugs involved.
pH and motility will unavoidably affect the absorption of
Similarly, drug–dietary chemical interactions (DDCI)
drugs. Despite a large number of drugs are absorbed via
will occur via these pathways leading to either beneficial
passive diffusion, alterations of intestinal influx and/or
or adverse effects. The current chapter mainly focuses efflux transporters also play an important role in the oral
on understanding the clinical occurrence and related absorption of certain drugs with transporters involved in
mechanisms of DDIs and DDCIs during the past three their absorption process. In addition, induction or inhi-
decades with the major interaction pathways covered bition of the intestinal metabolizing enzymes can also
in this chapter illustrated in Figure 26.1. In addition, modulate the first-pass metabolism in the GI tract, lead-
updates on drug interactions with therapeutic biolog- ing to significant alteration of drug bioavailability.
ics and interactions mediated by the gut microbiome
will be introduced. Based on the amount of clinical 26.2.1.1 Alteration of pH in the GI Tract
and mechanistic evidence available, DDIs along with pH of the GI tract can be influenced by drug, food,
major mechanisms will be discussed, with emphasis drink, or other xenobiotics. The most common perpetra-
on pharmacokinetics-based interactions during drug tor drugs, including antacids, proton pump inhibitors,
oral absorption, metabolism, and distribution, while and histamine H2 receptor antagonists, can increase
clinical-evidenced DDCIs of commonly used dietary gastric pH and lead to a pH-dependent dissolution
supplements will be highlighted. and subsequent changes in the bioavailability/systemic
Oral Bioavailability and Drug Delivery: From Basics to Advanced Concepts and Applications, First Edition. Edited by Ming Hu and Xiaoling Li.
© 2024 John Wiley & Sons, Inc. Published 2024 by John Wiley & Sons, Inc.
10.1002/9781119660699.ch26, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/9781119660699.ch26 by University Of British Columbia, Wiley Online Library on [28/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Drug A + Drug B /
I. Absorption III. Distribution and Elimination
Blood
BCRP P-gp OCT2 Apical
• Alteration of pH in GI tract GI tract
membrane
• Formation of insoluble complex in GI tract
• Modulation of gastrointestinal motility
• Alteration of intestinal transporter/microbiota Basolateral
membrane
Brain
Blood
Intestine Basolateral Blood
membrane OCT1 OCT2 OCT3 OAT1 OAT3 Basolateral
UGTs CYPs SULTs Kidney
membrane
PEPT1 ASBT MRP2 P-gp OATP2B1 Apical

BCRP Apical
membrane
P-gp BCRP MATE1 MATE2-K membrane
Lumen Urine
II. Metabolism
Blood
OCT1 OAT2 OATP1B1 OATP1B3
Basolateral
membrane
SULTs GSTs
Liver BSEP
CYPs BCRP P-gp
UGTs
Bile Apical
membrane
Bile UGTs
MRP2 SULTs
GSTs CYPs
Figure 26.1 Major pharmacokinetics based DDI and HDI pathways illustrated in this chapter.
26.2 Drug–Drug Interactions (DDIs) 503
Table 26.1 Summary of major pharmacokinetics drug–drug interactions in human based on their mechanisms.
Interaction types Interaction mechanisms Victim drug Perpetrator drug Outcomes of DDI References
Alteration of pH ↑ Gastric pH Cefpodoxime H2 Receptor ↓ 30 – 40% in F [2]

and formation of Proxetil, Antagonists
insoluble complex Cefuroxime Axetil,
in the GI tract Cefditoren Pivoxil
Cefdinir, Antacids ↓ 20 – 40% in F [2]
Cefpodoxime,
Cefditoren
Atorvastatin Antacids ↓ 38% in Cmax [3]
Cefpodoxime Famotidine, Maalox ↓ 40% in F [4]
Proxetil
Indinavir Omeprazole ↓ 50% in AUC [5]
Atazanavir Omeprazole ↓ 79% in F [5]
Lansoprazole ↓ 94% in F [6]
Ketoconazole Omeprazole ↓ 80% in AUC [7]
Fluvastatin Omeprazole, ↑ 43 – 70% in Cmax [8]
Cimetidine, Ranitidine and 24–33% in AUC
Capecitabine Proton Pump ↓ Plasma [9]
Inhibitors concentration
↑ Gastric pH and Enoxacin Maalox ↓ 73% in F [10]
Complex formation
Pefloxacin Aluminium, ↓ 56% in F [11]
Magnesium
Complex formation Ciprofloxacin Magnesium, ↓ 50 – 90% in Cmax [2]
Aluminum, Zinc, and AUC
Calcium,
Iron ↓ 57% in AUC [12]
Moxifloxacin Iron ↓ 39% in AUC
Sotalol Maalox ↓ 26% in Cmax and [13]
21% in AUC
Mycophenolate Iron Ion Preparations ↓ 90% in F [14]
Mofetil
Lomefloxacin Aluminium, ↓ 40% and 50% in [15]
Magnesium AUC and Cmax
Cimetidine Mylanta ↓ 23% in AUC [16]
Ranitidine Mylanta ↓ 26% in AUC [16]
Famotidine Mylanta ↓ 19% in AUC [16]
Nizatidine Mylanta ↓ 12% in AUC [16]
Modulation of GI ↓ GI motility Metformin Propantheline ↑ 19% in AUC [17]
motility
Desmopressin Loperamide ↑ 3.1-fold in AUC [18]
and 2.3-fold in Cmax
Alteration of Competition for P-gp Digoxin Talinolol ↑ 23% in AUC and [19]
intestinal 45% in Cmax
transporter
Atorvastatin ↑ 15% AUC and 20% [20]
in Cmax
↓ P-gp Fexofenadine Ketoconazole, ↑ 2.5-fold in Cmax [21]
Erythromycin
Digoxin Quinidine, Verapamil ↑ Cmax [21]
Ranitidine Ketoconazole ↑ 78% and 74% in [22]
Cmax and AUC
(continued)
504 26 Drug–Drug Interactions and Drug–Dietary Chemical Interactions
Table 26.1 (Continued)
↑ P-gp Ranitidine Rifampicin ↓ 53% and 52% in [22]

Cmax and AUC
Digoxin Rifampicin ↓ 30.3% and 58% in [23]
AUC and Cmax
Talinolol Rifampicin ↓ 35% in AUC [19]
↓ BCRP Topotecan Elacridar ↑ 1.8-fold in F [24]
Alteration of ↑ CYP3A and P-gp Itraconazole, Rifampin ↓ Cmax up to 70% [2]
first-pass Ketoconazole,
metabolism via Voriconazole,
interplay between Diltiazem,
CYP3A4 and P-gp Verapamil,
Metoprolol,
Propranolol,
Carvedilol,
Doxycycline,
Fluconazole
Cyclosporine Rifampin ↓ 3.7 in F and [25]
2.8-fold in Cmax
Nifedipine Rifampicin ↓ eightfold in F [26]
↓ CYP3A and P-gp Lovastatin Cyclosporine, ↑ 20-fold in AUC [26]
Itraconazole
Atorvastatin Erythromycin ↑ 38% in Cmax and [16]
33% in AUC
Cyclosporine Ketoconazole ↑ 5.3 in F and [25]
2.7-fold in Cmax
Interactions Competition on Nevirapine Mefloquine ↓ 47% in median [27]
involving liver CYP3A4 plasma
metabolic enzymes concentration
↑ CYP3A4 Bedaquiline Rifampin ↓ 45% in AUC [28]
↓ CYP3A4 Midazolam Erythromycin, ↑ 2–6 fold in AUC [2]
Clarithromycin,
Telitheromycin
Simvastatin Erythromycin, ↑ 4–8 fold in AUC [2]
Clarithromycin,
Telitheromycin
Cyclosporine, Erythromycin, ↑ 2–6 fold in Cmax [2]
Tacrolimus Clarithromycin
Clopidogrel Ritonavir and ↓ 69% in AUC of the [29]
Cobicistat active metabolite
Prasugrel Ritonavir and ↓ 52% and 41% in [29]
Cobicistat AUC and Cmax of
active metabolite
Docetaxel Ritonavir ↑ 590% in AUC [30]
Ketoconazole ↑ 210% in AUC
Atorvastatin Itraconazole ↑ 63% in AUC [31]
↓ CYP3A5 Cyclosporine Amlodipine ↑ the plasma [32]
concentration
↓ CYP2D6 Metoprolol Diphenhydramine ↓ 60% metabolic [33]
clearance in
extensive
metabolizers
Ecstasy Paroxetine ↑ 30% in Cmax [34]
(continued)
Nebivolol Paroxetine ↑ 510% in AUC [35]

Atomoxetine Paroxetine ↑ 550% in AUC [36]
Fluvoxamine ↑ 133% in AUC [37]
↓ CYP2D6 and Atomoxetine Bupropion ↑ 71% and 410% in [38]
UGT2B10 Cmax and AUC
↑ CYP2C9 Phenytoin Lopinavir and ↓ 23% in AUC [39]
Ritonavir
↑ CYP2C9 and Voriconazole Ritonavir ↓ 66% and 82% in [40]
CYP2C19 Cmax and AUC
Interactions involving ↓ OATP1B1 Ambrisentan Clarithromycin ↑ 27 % in Cmax [41]
transporters in liver,
kidney and other
organs
↓ OATP1B1 Pravastatin Ritonavir ↑ 113 % in AUC in [42]
slow elimination
population
↓ OCT2 Metformin Cimetidine ↑ 20 % in AUC in [43]
slow elimination
population
↓ OCT2 and MATE1 Metformin Ranitidine ↓ 15 % in renal [44]
clearance in slow
elimination
population
↓ OATP2 Rosuvastatin Gemfibrozil ↑ 121% and 88% in [45]
Cmax and AUC
exposure of the victim drugs. Various clinical reports subsequent 50% reduction in its oral bioavailability in
on oral drug absorption influenced by the alteration of healthy volunteers [5]. Coadministration with omepra-
pH in the GI tract are listed in Table 26.1. Oral bioavail- zole or lansoprazole could lead to a potential virologic
abilities of cephalosporin antibacterial agents, such as failure of atazanavir due to up to 79–94% reductions in
cefpodoxime proxetil, cefuroxime axetil, and cefditoren its oral bioavailability [5, 6]. In addition to antibiotics
pivoxil, could be significantly reduced by 30–40% when and protease inhibitors, oral absorptions of several
coadministered with perpetrator drug such as his- statins including atorvastatin and fluvastatin were
tamine H2 receptor antagonist famotidine due to their found to be influenced by gastric pH. Coadministered
decreased solubility at the increased gastric pH [2, 4]. oral antacid suspension containing magnesium and
Similarly, presence of antacid during the treatment
aluminum hydroxides could significantly decrease the
with antibiotics, such as cefaclor, cefdinir, cefpodoxime,
plasma concentrations of both atorvastatin and its active
and cefditoren, could lead to 20–40% reduction in oral
metabolites by approximately 38% due to the reduced
bioavailabilities of these victim antibiotics in human
dissolution of atorvastatin in GI tract in presence of
subjects [2]. Besides antibiotics, the gastric solubilities
these antacids [3]. In contrast, coadministered his-
of victim drugs such as viral protease inhibitors are also
pH dependent with decreased oral absorption observed tamine H2 -receptor antagonist, including omeprazole,
when gastric pH increased. Drugs such as antacids, cimetidine, or ranitidine, could increase gastric pH and
H2 receptor antagonists, and proton pump inhibitors, reduce the GI tract degradation of fluvastatin, leading to
which increase gastric pH may reduce the solubilities its significantly increased Cmax (from 43% to 70%) and
of the protease inhibitors in the GI tract. For example, AUC (from 24% to 33%) [8, 46]. A more recent study
coadministered omeprazole could decrease the aqueous found coadministered proton pump inhibitors could
solubility of indinavir from more than 100 mg/ml at also reduce the systemic exposure of orally administered
pH 3 to less than 0.1 mg/ml at pH 5, leading to the chemotherapy drug capecitabine [9].
26.2.1.2 Formation of Insoluble Complex in GI Tract and hydroxy-methylglutaryl coenzyme A reductase

Since antacids and sucralfates contain multivalent inhibitors and atorvastatin, may cause DDIs when they
cations such as aluminum, magnesium, zinc, calcium, are administered together. Competition for the intesti-
and iron, they would chelate the victim drugs to form nal P-gp transporter, an efflux transporter located at
insoluble complexes in the upper GI tract, resulting in the apical side of the intestinal epithelium membrane,
their reduced oral absorptions. As listed in Table 26.1, during their absorption in the small intestine could
the commonly reported victim drugs include H2 recep- lead to significantly increased oral bioavailability of
tor antagonists and various antibiotics, in particular coadministered digoxin and talinolol [19] or 15% and
quinolones and tetracyclines. Area under the curve 20% rise in the AUC and Cmax of digoxin in presence
(AUC) for plasma concentrations versus time profiles of atorvastatin [20]. As also indicated in Table 26.1,
of H2 -receptor antagonists, cimetidine, ranitidine, clinically significant DDIs have been observed with
nizatidine, and famotidine decreased by 23%, 26%, the involvement of perpetrator drugs that are P-gp
12%, and 19%, respectively, when coadministrated with inhibitors, such as ketoconazole, erythromycin, ver-
antacid Mylanta [16]. Tetracyclines are also prone to apamil, quinidine, probenecid, and cimetidine [21].
react with antacids, forming insoluble or poorly soluble Besides, P-gp has been shown to be inducible by per-
chelates that lead to a significant reduction in their petrator drugs including rifampicin, phenobarbital,
oral absorption in the GI tract [47]. Besides, fluoro- dexamethasone, isosafrole, clotrimazole, and reserpine
quinolone antibacterial drugs interact with multivalent [21]. Pretreatment with rifampicin resulted in a 3.5-fold
cation-containing agents to form insoluble complexes, increase in intestinal P-gp levels, leading to significantly
leading to up to 90% reduction in their plasma Cmax and decreased AUC (30.3%) and Cmax (58%) of coadmin-
AUC [2, 14]. istered digoxin in healthy volunteers [23]. Moreover,
nine consecutive days pre-treatment with rifampicin
26.2.1.3 Modulation of Gastrointestinal Motility
(600 mg/day) could induce intestinal P-gp level for
The rate and extent of oral absorption of many drugs can
4.2-fold and thus decrease the serum AUC (35%) of
be significantly affected by the alteration of GI motility,
coadministered talinolol, a P-gp substrate [19].
such as the increase in the rate of gastric emptying and
In addition to P-gp, BCRP also has the potential
upper intestinal motility by GI prokinetic agents. Half
to impact the oral bioavailability of its substrates.
an hour of pretreatment with propantheline in healthy
For example, Elacridar could inhibit the intestinal
volunteers prolonged gastric emptying and intestinal
BCRP, leading to the increased bioavailability of coad-
transit time, resulting in 19% increase in the plasma
ministered topotecan to 2.8-fold [24]. Besides, other
AUC of the coadministered metformin [17]. Similarly,
transporters expressed in the intestine include PEPT1,
pretreatment with loperamide could also slow the GI
MRP2, OCT1, and OATPs and potential DDIs related
motility, leading to the 3.1- and 2.3-folds increase in
to these transporters are also worth of investigation,
plasma AUC and peak/maximum concentration (Cmax )
especially for drugs with low membrane permeability.
of co-treated desmopressin, respectively, but the time
According to the FDA guidance, a drug candidate,
to reach the T max was markedly longer indicating the
decreased rate of absorption [18]. which is a major P-gp or BCRP substrate with poor
membrane permeability or solubility, is recommended
26.2.1.4 Alteration of Intestinal Transporters to perform clinical drug–drug interaction study based
During drug absorption process, lipophilic drugs are on its safety margin, therapeutic index, and likely
absorbed mainly by passive diffusion, whereas absorp- concomitant medications [48].
tion of a number of aqueous soluble drugs are generally
mediated by active influx and efflux transporters in 26.2.1.5 Alteration of Intestinal First-Pass
the small intestine. Inevitably, DDI will take place Metabolism Via Interplay Between Metabolic Enzymes
when coadministered multiple drugs are substrates and Transporters (see also Chapter 23)
of the same transporters. In addition, certain drugs It has been extensively reported that the metabolizing
could inhibit or induce activity of the specific trans- enzymes such as CYP3A4 and P-gp expressed in the
porters, which may also lead to interactions with other small intestinal epithelial cells could possibly interplay
drugs that are substrates of the transporters involved. during oral absorption process of a drug. The spatial
Among all the transporters involved in the absorption relationship of P-gp across the plasma membrane and
processes, P-glycoprotein (P-gp) has been investigated CYP3A4 inside the cell on the endoplasmic reticulum
most extensively. Many P-gp substrates drugs includ- suggests that P-gp may act to regulate the exposure of
ing digoxin, talinolol, clarithromycin, dipyridamole, substrate drugs to the CYP3A4-mediating metabolism
in small intestinal epithelial cells. P-gp and CYP3A4 In addition to CYPs, intestinal phase II metabolism
share many substrates and inhibitors and their common enzymes such as UDP-glucuronosyltransferases (UGTs)
substrates can be absorbed via passive diffusion or pos- and sulfotransferases (SULTs) also contribution to
sibly through an influx transporter into the enterocytes the metabolic barrier in the intestine. The UGT1 and
from lumen of the small intestinal tract, and then be UGT2 families are primarily enzymes involved in drug
moved directly into the systemic circulation or metab- glucuronidation. Among them, UGT1A1, UGT1A6,
olized by CYP3A4 in the enterocytes or secreted back UGT1A10, UGT2A3, UGT2B7, and UGT2B17 are the
into the intestinal lumen via P-gp. Drug that is pumped most abundant within small intestine [50]. UGTs are
back into the lumen can be reabsorbed at a distal site sensitive to induction and inhibition by xenobiotics.
of the small intestine and enter the systemic circulation SULT1B1 and SULT1A3 are the two predominant
again, which creates a cycling effect. If one such drug is SULTs in the small intestine, accounting for 36 and 31%
given concurrently with perpetrator drug that inhibits of the total, respectively [50]. SULTs are less responsive
both P-gp and CYP3A4, such as ketoconazole, increased to induction than CYPs and UGTs [51]. Although many
oral absorption and bioavailability of the victim drug inhibitors/inducers on UGTs and SULTs have been
will be observed. P-gp is considered as a “gate keeper” reported based on their in vitro activity [52, 53], clinical
for the drug exposure to the later CYP3A4-mediating evidences supporting the intestinal DDIs mediated by
reactions in the cycling process. UGTs or SULTs are rare. Further studies on potential
The common substrates shared by CYP3A4 and DDIs related to these enzymes are warranted.
P-gp include colchicine, cortisol, cyclosporine, dilti-
azem, etoposide, nicardipine, paclitaxel, rapamycin, 26.2.1.6 Alteration of Intestinal Microbiota (see also
saquinavir, tacrolimus, verapamil, and vinca alka- Chapter 25)
loids, while dexamethasone, phenobarbital, phenytoin, It is well known that intestinal microbiota can mediate
rifampin are the examples of their common inducers drug metabolism including reduction, oxidation, dehy-
[25]. Although concurrent administration of either droxylation, and decarboxylation. In recent decade,
two of such substrates has a potential to cause inter- intestinal microbiota has been identified as a vital drug
actions, the clinically significant DDIs are mainly target in many disease treatments and its changes in
resulted from the preparator drugs as the inducers or the GI tract may influence the metabolism of adminis-
inhibitors of CYP3A4 and/or P-gp systems rather than tered drugs, leading to their altered pharmacokinetics
their substrates only. Coadministration with rifampin, [52]. Unlike inhibition of metabolizing enzymes or
an inducer for both CYP3A4 and P-gp, could reduce transporters, alteration of intestinal microbiota may
the oral bioavailability and the Cmax of cyclosporine sustain even after the elimination of administered
by about 3.7-fold and 2.8-folds, respectively, due to the antibiotics from the intestine. Among the intestinal
increased apical efflux and first-pass metabolism in the microbiota-mediated DDIs, interactions with antibi-
GI tract [25]. Due to significant induction of the P-gp otics are most reported. Many antibiotics can disturb
-mediated transport and CYP3A4-mediated first-pass the pharmacokinetics of a coadministered drug via
metabolism in both intestine and liver, rifampin could alterations on the enzymatic activities and composition
significantly decrease the oral bioavailability of the of gut microbiota [54], leading to potential therapeu-
coadministered nifedipine by almost eightfold, [26]. tic effect changes. Research has demonstrated that
On the other hand, concomitant administration of two-thirds (176 out of 271 tested) of the assayed orally
CYP3A4 and P-gp inhibitors could enhance the oral administered drugs are metabolized by at least one
bioavailability of victim drugs, which are the sub- bacterial strain among 76 human gut bacteria [55].
strates of both P-gp and CYP3A4. Ketoconazole, the Some of the metabolism have shown specificity to
inhibitor for CYP3A4 and P-gp, significantly increased chemical structures. For example, Bacteroidetes strain
the oral bioavailability and Cmax of coadministered specifically hydrolyze drugs that contain ester or amide
cyclosporine by about 5.3-fold and 2.7-fold, respectively groups. Compounds that are metabolized by most
[25]. Tacrolimus is a substrate of both CYP3A4 and P-gp other bacteria contain a nitro or azo group, which
and its oral bioavailability could be markedly increased is prone to reduction in anaerobic metabolism [55].
in the presence of preparator drug ketoconazole, which Metabolism of sulfinpyrazone to sulfinpyrazone sulfide
could significantly inhibit its P-gp-mediated transport in the gut contents and their plasma pharmacokinetic
and/or the CYP3A4-catalyzed metabolism in the small profiles were found to be altered in patients with the
intestine [49]. antibiotic metronidazole treatment [56]. In addition,
altered microbiota composition may also lead to phar- (CYP3A4, 1A2, etc.) have been revealed and certain
macodynamics changes in the concomitant drugs. single nucleotide polymorphisms had a significant
It was noticed that the presence of a certain type of impact on P450 expression, clinical studies on DDIs
bacteria may have an impact on chemotherapy and mediated by such CYPs often take such polymorphisms
immunotherapy [57, 58]. Clinical trials are currently into considerations to identify the potential exten-
conducted on microbiota interventions, such as probi- sive or poor metabolizer populations for safe use of
otics and fecal microbiota transplant, to explore their medication.
influence on the efficacy and toxicity of coadministered Besides CYPs, conjugative enzymes including
chemotherapeutic agents, immunotherapeutic agents, UDP-glucuronyltransferases (UGTs), sulfonyl trans-
and anti-inflammatory drugs [59]. ferases (SULTs), and glutathione S-transferases (GSTs)
mainly mediate the phase II reactions. Among the
UGTs, UGT1, and UGT2 families are glucuronida-
26.2.2 Pharmacokinetics Interactions Involving
tion enzymes involved in many reported DDIs [65].
Liver Metabolic Enzymes
For example, the systemic exposure of atomoxetine is
Since metabolic enzymes, including Phase I and Phase increased 410% by co-treatment of Bupropion, which
II, play an extremely important role in pharmacokinetics is believed a combined result of the inhibition of
of drugs, understanding variation in their activity is cru- glucuronidation as well as CYP2D6 [38].
cial for better understanding related DDIs and improv-
ing the clinical use of drugs. Advances are being made
26.2.3 Pharmacokinetics Interactions Involving
in understanding the role of specific Phase I and Phase
Transporters in Liver, Kidney, and Other Organs
II enzymes in the pharmacokinetic-based DDIs as listed
in Table 26.1 and illustrated below. Since transporters control the uptake and efflux of
Among all the isoforms of enzymes involved in drugs and serve as the gatekeepers for cells, alter-
DDIs, cytochrome P450s (CYPs) are the ones being ation of their function or expression may significantly
investigated the most as shown in Figure 26.1. As the change the systemic and tissue exposure of drugs,
major Phase I enzyme, CYPs mediates the oxidization leading to significant changes in pharmacokinetics.
of foreign substances to enhance their aqueous sol- As shown in Table 26.1, induction or inhibition of
ubility for elimination from the body with CYP1 to transporters by coadministered drugs can induce phar-
CYP4 families focusing on oxidation of both exogenous macokinetics and pharmacodynamics DDI. Unlike the
and endogenous substrates [31, 52, 60–64]. CYP1A2, alteration of metabolic enzymes, which can be directly
CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP2B6 observed from clinical studies via the changes of phar-
covered 75.9% of the hepatic CYPs enzymes in abun- macokinetic profiles of the metabolites, modulation
dance and accounted for the metabolism of 97% of of transporters-mediated DDI are often evidenced by
marketed drug. Among these isoenzymes, CYP3A plays pre-clinical studies using cell lines or transgenic ani-
the most important role in drug hepatic metabolism mals based on their strong indications of transporters’
and is involved in many reported DDIs. Table 26.1 involvement from the clinical DDIs studies.
summarized the human studies with significant DDIs Figure 26.1 also summarizes the transporters in
induced by the substrates and inducers of CYP3A4. major organs that could be affected by drugs, leading to
For example, the plasma concentrations of docetaxel, selective distribution of drugs to specific tissues. Efflux
a substrate of CYP3A4, can be significantly increased transporters like P-gp and BCRP on the blood–brain
by three and sixfold by CYP3A inhibitors ritonavir barrier can suppress the distribution of drugs into
and ketoconazole, respectively [30]; while the systemic the brain, whereas the uptake transporters such as
exposure of another CYP3A4 substrate, bedaquiline OCT2 could play key roles in the uptake of neuroactive
can also be reduced by 45% when coadministrated drugs such as serotonin, norepinephrine, dopamine,
with CYP3A4 inducer rifampin [28]. Besides CYP3A4, choline, and histamine into the brain. In addition,
CYP2D6 has also been found mediating many DDIs. transporters located in liver and kidney played primary
The CYP2D6 inhibitor paroxetine can significantly roles in drug elimination. Since P-gp is responsible
induce the systemic exposure of coadministrated for the biliary excretion of drugs such as amphiphilic
drugs (including ecstasy, nebivolol, and atomoxe- cationic drugs including doxorubicin, digoxin, and
tine) to up to sixfold, leading to undesired adverse vinblastine, its inducer/inhibitor can not only alter the
effects [34–36]. Since large variations in protein con- intestinal absorption but also the biliary excretion of
tent, mRNA levels, and intrinsic activities of 10 P450s these drugs. Compared to the DDI reports on P-gp,
clinical evidence on DDIs mediated by other efflux compared with carriers of GG genotype after treatment
transporters such as BCRP, MRP2, and MRP4 remain with the OCT2 and MATE1 inhibitor ranitidine [44].
limited.
In addition to above-mentioned efflux transporters,
26.2.4 Pharmacokinetics and
the SLC superfamily (including OAT, OCT, and OATP
Pharmacodynamics Interactions Between Drugs
families) transporters are responsible for drug uptake and Biologics
into hepatocytes and active secretion/reabsorption of
drugs in the proximal tubule region of kidney. Among With the growing development of therapeutic biologics
these transporters, OATP1B1/1B3 highly expressed in including therapeutic proteins, monoclonal antibodies
liver are considered to be of particular importance for (mAbs), vaccines, and peptide and nucleic acid deriva-
hepatic drug elimination and related DDIs. Gemfibrozil tives, the risk of DDIs with biologics is increasing in
and clarithromycin were found to significantly increase clinical practice. The pharmacokinetics of biologics is
the Cmax and AUC of coadministered rosuvastatin and generally quite different from those of small molecules.
ambrisentan via inhibiting their OATP2 and OATP1B1 To avoid rapid degradation in the gastrointestinal tract
mediated hepatic eliminations, respectively [41, 45]. after oral administration, most of the therapeutic bio-
The OCTs and MATE families expressed in kidney are logics are administered via alternative routes including
responsible for renal secretion of a variety of drugs. Ran- intravenous, intramuscular, and subcutaneous injec-
itidine could inhibit the OCT2 and MATE1-mediated tions. Since the distribution of therapeutic biologics is
mainly mediated by interstitial penetration, lymphatic
kidney elimination of metformin leading to reduction
drainage, transcytosis, and receptor-mediated cell
in its renal clearance [44].
uptake, therapeutic proteins usually have a limited
It is known that groups of transporters and metabo-
volume of distribution and do not bind to plasma
lizing enzymes including phase I enzymes (e.g. CYPs),
proteins with negligible biliary and renal excretion.
phase II enzymes (e.g. UGTs and GST), and transporters
Besides catabolism via proteolytic degradation, target
(e.g. P-gp, BCRP, OATPs, and MRP2) are regulated by
antigen-mediated disposition also plays a role in the
the nuclear receptors PXR and CAR [66]. These nuclear
elimination of therapeutic proteins [52, 67]. Fragment
receptors can be activated by administered drugs, lead-
crystallizable receptor-mediated antibody recycling
ing to the induction of related proteins. The expression
by monocytes, macrophages, and dendritic cells is a
of CAR and PXR is tissue specific. Both PXR and CAR
salvage pathway that could prolong the half-lives of
are expressed in the liver. CARs have little extrahepatic
many mAbs. Since immune responses participate in
expression. PXRs are also expressed in the intestine,
both the catabolism and the antibody recycling pro-
while its expression in the kidney is significantly lower cess, immunogenicity can significantly influence the
than that in liver. Therefore, DDIs involving transporter clearance of therapeutic proteins [68]. Compared to
or enzyme inducers highly depend on the induction therapeutic proteins, nucleic acid and peptide drugs
mechanism as well as the tissue concentrations of the with high plasma binding undergo much slower renal
inducers. Generally, inducer activate CARs may have excretion with elimination mainly by peptidases and
major effect on the liver, while activator of PXRs may nucleases [67, 69].
alter the expression levels of transporters and enzymes Although direct competition between therapeutic
in both liver and intestine [66]. biologics and small molecules is not likely due to their
It was also noticed that some transporter-mediated distinct pharmacokinetic properties, DDIs may still
DDIs can only be observed when genetic polymor- occur via indirect pathyways. It was reported that cer-
phisms of transporters are taken into consideration. For tain biologics with immunomodulatory effects could
example, an 808G > T genetic variation of OCT2 has alter CYP activities via modulating the cytokine levels
been found to be associated with a reduced metformin and result in pharmacokinetics changes for victim drugs
renal clearance. Coadministration of cimetidine in that are substrates of the related CYPs [70]. According
patients carrying this genetic variation can lead to 30% to the newest FDA guideline on DDIs of therapeutic
decrease in renal clearance and 20% increase in the proteins, such CYP-mediated DDIs are based on three
AUC of metformin [43]. In other situation, reduced types of mechanisms: (i) the therapeutic protein is a
function variants do not show any significant pharma- proinflammatory cytokine, (ii) the therapeutic protein
cokinetic change until after the addition of inhibitors. can cause an increase in proinflammatory cytokine
The subjects with MATE1 variant rs2289669 (G > A) levels, and (iii) the therapeutic protein can modulate
only had significantly lower metformin renal clearance proinflammtory cytokines in conditions with elevated
cytokine levels [64]. Since tocilizumab could induce reported interactions that would lead to various unde-
CYP3A4 activity via decreasing interleukin 6 levels, sirable effects. The uniqueness of dietary supplement
it could reduce the systemic exposure of coadminis- is that they quite often exist as a mixture of different
tered CYP substrate drug simvastatin [71]. Similarly, dietary chemicals or an extract from various herbal
influenza vaccination has been reported to decrease plants with dosage forms like tablet or capsule. How-
CYP activity by triggering inflammation, such that it ever, the identities of the active components and/or the
could affect the systemic exposure of CYP substrate quantities of each active component in the mixture or
drug clozapine [72]. the extract are not always fully specified and the wide
Besides affecting cytokine levels, therapeutic proteins variation between different batches of herbal products
may also alter pharmacokinetic profiles of coadminis- also leads to poor reproducibility of the tests, which
tered small molecules via changing the physiological became the biggest barrier for the mechanistic studies
processes in human. GLP-1 receptor agonists such of DDCIs. Unlike the DDIs, due to the complexity of
as dulaglutide and albiglutide could delay the gastric the components in the dietary supplements and limited
emptying and immunosuppressive agents may decrease studies on the detailed pharmacokinetic parameters
the immunogenicity of the therapeutic protein [64]. of specific dietary chemicals, very limited studies have
Immunosuppressant methotrexate could decrease the reported the related pharmacokinetic changes of the
clearance of coadministered mAbs including infliximab specified dietary chemicals. Regardless, the level of
[73], golimumab [74], and adalimumab [75]. evidence on DDCIs is still insufficient. Although the
Similar to DDIs for small molecule drugs, pharmaco- clinical evidenced DDCIs studies are getting more and
dynamics-based DDIs of therapeutics biologics are more more, majority of their clinical studies were conducted
commonly reported than their pharmacokinetics-based in healthy populations, where the impact of the herbs
DDIs. Owing to their complex signal pathways, insulin on the pharmacodynamics effects of the concurrent
could interact with numerous drugs, including hor- drug may not be determined. DDCIs basically share the
mones, antidiabetics, antibiotics, and antipsychotics, same mechanisms as DDIs. Alteration of pH in the GI
and recombinant growth hormones could interact with tract and gastrointestinal motility was barely reported.
small molecule hormones such as glucocorticoids, To avoid physio–chemical interactions between herbal
estrogens, and thyroxin [52, 68]. Although DDIs among components and drugs, it is usually recommended that
biologics with similar indications usually result in herbs should be taken two hours before or after the
additive or synergistic efficacy, they may also induce drugs.
toxicity. Combination use of anakinra and etanercept As summarized in Table 26.2, majority of the clinical
could lead to severe adverse effects including increased evidenced DDCIs are related to the alteration of liver
risk of infection and neutropenia without significant metabolic enzymes and transporters. Regarding the
improvement in the rheumatoid arthritis treatment [76]. victim drugs involved in DDCIs, effect of herbs/herbal
components on the pharmacokinetics and pharmaco-
dynamics of drugs with narrow therapeutic indexes,
especially drugs for CNS and cardiovascular diseases,
26.3 Drug–Dietary Chemical are often reported [116]. Among all the clinically evi-
Interactions in Oral Bioavailability denced DDCIs, garlic, pepper, St John’s Wort, ginkgo
biloba, ginger, ginseng, curcumin, grapefruit juice,
Dietary supplements, containing dietary chemicals and vitamins are the most commonly reported ones
with identified structures as their major ingredients, with possible mechanisms investigated and highlighted
were defined by FDA as the products such as herbals, below, whereas other commonly used dietary supple-
vitamins, minerals, and other products that people use ments such as milk thistle, cranberry juice, and black
in addition to the foods they eat. During the past two cohosh extract seem to have minimal impact on their
decades, supported by more and more clinical evidence, coadministered drugs.
drug–dietary interactions, regardless of the mechanism
involved, are frequently reported as a potential contrib-
utor to the altered therapeutics of drugs. Nowadays, it is
26.3.1 Garlic
common to see cautions for the potential drug–dietary
chemical interactions appeared in the package labeling Garlic is one of the most popular dietary substances
and/or inserts of a number of medications. Despite with various beneficial effects. Coadministrations with
some of the interactions are beneficial, most cases garlic have been reported to alter pharmacokinetics of
Table 26.2 Summary of major dietary product with Drug–dietary chemical interactions in human.
Dietary Substance Dose and Victim drug (dose Effect of Potential

supplements (Content)/Component Dosing frequency and dosing frequency) interactiona mechanismb References
Garlic Extract (NA) 1 caplet, BID, day 5∼25 Saquinavir (1200 mg, TID, ↓ 51% in AUC and 54% in ↑ CYP3A4 [77]
day 1∼4, 22∼25, and Cmax
36∼39)
Enteric-coated garlic 1 tablet, BID, 2-week Rac-warfarin (25 mg) = PK NA [78]
tablets (2000 mg of
fresh garlic bulb;
3.71 mg of allicin per
tablet)
Pepper Piperine (NA) 20 mg, QD, 7-day Propranolol (40 mg) ↓ T max , Cmax and AUC ↓ CYP1A1 [79]
Theophylline (150 mg) ↑ Cmax and AUC ↓ CYP1A2
1g Phenytoin (300 mg) ↑ AUC ↓ P-gp [80]
Kava kava rhizome 1227 mg, TID Midazolam (8 mg) = PK Not a potent CYP3A [60]
extract (75 mg inhibitor in vivo
kavalactones per
capsule)
136.3 mg, TID, 14-day Debrisoquine (5 mg) = Debrisoquine urinary Not a potent CYP2D6 [61]
recovery ratios inhibitor in vivo
St John’s Wort Extract (NA) 300 mg, TID Cyclosporine (NA) ↓ 47% in steady state ↑ CYPs [81]
concentration
300 mg, TID, 14-day Indinavir (800 mg) ↓ 57% in AUC ↑ CYPs [82]
Alprazolam (2 mg) ↓ twofold in AUC ↑ CYPs [62]
Digoxin (0.5 mg) ↓ 18% in AUC ↑ P-gp [83]
300 mg, TID, 30-day Fentanyl (NA) = PK Not known [84]
Extract (3% hyperforin) 300 mg, TID, 14-day Debrisoquine (5 mg) = Debrisoquine urinary Not a potent CYP2D6 [61]
recovery ratios inhibitor in vivo
Jarsin 300® (NA) 300 mg, TID, 12-day Talinolol (50 mg, po) ↓ 25% in AUC ↑ P-gp [85]
Talinolol (30 mg, iv) ↑ 35% in CLnonrenal
(continued)

Ginkgo Biloba Extract (NA) 140 mg, BID, 12-day Omeprazole (40 mg) ↓ AUC ratio of ↑ CYP2C19 [86]
omeprazole/5-OH
omeprazole
120 mg, BID, 2-week Midazolam (8 mg) ↓ 34% in AUC and 31% in ↑ CYP3A [87]
Cmax
Fexofenadine (120 mg) = PK NA
360 mg, QD, 14-day Talinolol (100 mg) ↑ 22% in AUC and 36% in ↓ P-gp [88]
Cmax
Curcumin Nanoparticles 3 g, QD, 12-week Acitretin (0.4 mg/kg, = Cholesterol serum levels NA [89]
QD, 12-week)
ZhiKePing, 300 mg, QD, 6-day Talinolol (50 mg) ↓ AUC and Cmax ; ↑ CL/F May relate to [90]
upregulation
50 mg capsule of further
contained ATP-binding
demethoxycurcumin cassette
and bisdemethyoxycur- transporters
cumin
Curcuma rhizomes Extract (NA) 1.5 g, BID, 7-day Dextromethorphan ↑ Urinary metabolic ratio ↓ CYP2D6 [91]
(30 mg) of dextromethorphan
/dextrorphan
Grapefruit juice NA Cyclosporine (5 mg/kg) ↑ 45% in AUC ↓ CYP3A4 [92]
240 ml, 7-day Terfenadine (60 mg, ↑ AUC and Cmax ↓ CYP3A4 [93]
BID, 14-day)
NA Midazolam (NA) ↑ AUC ↓ CYP3A4 [94]
250 ml, 13∼38 days Diltiazem (120 mg) ↑ 20% in AUC ↓ P-gp or [95]
CYPs
200∼300 ml Felodipine (10 mg) ↑ 47% in AUC and 50% in ↓ CYP3A4 [96]
Cmax
Caffeine 1.5 g/m2 /day, 3-day Cisplatin (120 mg/m2 , Radiographic responders NA [97]
continuously, 2∼5 courses, intra-arterial, 1-day, at stages II and III were
2-week intervals from 2∼5 courses, 2-week significantly improved
June 1989 to Dec 1991 intervals) compared to the
non-responders (p = 0.004
and p = 0.034)
1.5 g/m2 /day, 3-day Cisplatin (120 mg/m2 ,
continuously, 2∼5 courses, 1-day); Doxorubicin
3-week intervals from Jan (30 mg/m2 /day, 2-day);
1992 to Dec 1995 2∼5 courses, 3-week
intervals
1.5 g/m2 /day, 3-day Cisplatin (120 mg/m2 ,
continuously, 3∼5 courses, 1-day); Doxorubicin
3-week intervals from Jan (30 mg/m2 /day, 2-days)
1996 to Dec 1998 after radiation therapy
(2 Gy/day, 5-day); 3∼5
courses, 3-week
intervals
Vitamin Vitamin D 100000 U bolus Budesonide or ↑ Forced expiratory NA [98]
intramuscularly + 50000 U budesonide + volume in 1 second [FEV1 ]
orally weekly, 24-week formoterol (NA)
- Improved fasting blood
Vitamin C 500 mg, BID, 90-day Metformin (500 mg, sugar, HbA1c, lipid pro- NA [99]
BID, 90-day) file, insulin, homeostasis
model assessment of
insulin resistance;
- Reduced glutathione and
Quantitative
Insulin
Sensitivity
Check
Index
Vitamin E 400 mg, BID, 90-day
Vitamin C + Vitamin E Vitamin C 500 mg +
Vitamin E 400 mg, BID,
90-day
Vitamin Vitamin B12 + Folic Vitamin B12 1000 μg, Gemcitabine = PK NA [100]
acid every 9 weeks, starting 1 (1250 mg/m2 , iv, day-1
week before and 8);
chemotherapy, finishing at
Cisplatin (80 mg/m2 ,
least 3 weeks after the last
iv, day-1 in a 3-weekly
treatment dose;
cycle)
Folic acid 450 μg, starting
at least 1 week prior to
chemotherapy, finishing at
least 3 weeks after the last
treatment dose
(continued)

Folic acid 0.8 mg, median 4.4-year Enalapril (10 mg, ↓ Development of NA [101]
median 4.4-year) proteinuria in diabetic
patients with hypertension
Milk thistle Silymarin 140 mg; 4 capsules Nifedipine (10 mg) = Absorption or Not a potent [102]
173.0∼186.7 mg dry metabolism of nifedipine CYP3A4
extract of milk thistle inhibitor in
per capsule vivo
80% silymarin per 300 mg, TID,14-day Debrisoquine (5 mg) = Debrisoquine urinary Not a potent [61]
capsule recovery ratios CYP2D6
inhibitor in
vivo
Black cohosh Extract (2.5% 40 mg, BID, 14-day
triterpene glycosides
per tablet)
Echinacea purpurea Extract (2.2 mg 267 mg, TID, 14-day
isobutylamides per
capsule)
Extract (NA) 20 drops, TID, day-7 to Docetaxel (135 mg, iv, = PK NA [103]
day-21) day-1 and 22)
Echinacea 600 mg of E. 1275 mg, QID, 7-day Warfarin (25 mg) ↓ AUC of (S)-warfarin NA [104]
angustifolia roots and
675 mg of E. purpurea
root
Cranberry juice 500 mg cranberry juice 2 capsules, TID, 2-week Rac-warfarin (25 mg) = PK NA [78]
concentrate per tablet
27% cranberry 180 ml, BID, 5-day Diclofenac (25 mg) Not a potent [105]
CYP2C9
modulator in
vivo
Resveratrol NA 500 mg, QD, 10-day Chlorzoxazone ↑ AUC and Cmax ; ↓ CL/F ↓ CYP2E1 [106]
(250 mg)
Diclofenac (100 mg) ↑ AUC and Cmax ; ↓ CL/F ↓ CYP2C9 [106]
Shiitake mushroom NA 250 g, TID, 1-day Gabapentin (600 mg) ↓ Cmax NA [107]
Goldenseal (Hydrastis canadensis) Root extract (24.1 mg 1070 mg, TID, 14-day Debrisoquine (5 mg) ↓ Debrisoquine urinary ↓ CYP2D6 [61]
isoquinoline alkaloids recovery ratios
per capsule)
1323 mg, TID, 14-day Midazolam (8 mg) ↑ AUC and Cmax ; ↓ CL/F ↓ CYP3A [60]
Radix astragali Extract granules (NA) 4 g, BID, 7-day Fexofenadine (120 mg) = Systematic exposure of Not a potent [108]
fexofenadine modulator of
P-gp in vivo
Radix/rhizoma notoginseng Extract (Sanchitongshu 1 capsule (200 mg), QD, Aspirin (50 mg, QD, Ameliorated neurological NA [109]
capsule: 100 mg 28-day 28-day) deficit (increased score of
panaxatriol saponin ESS: t = −5.02, p < 0.0001)
contained 50% and activities of daily
Ginsenoside Rg1, 6% living (increased score of
Ginsenoside Re, 11% BI: t = −2.4, p = 0.0178)
Notoginsenoside R1
per capsule)
Schisandra sphenanthera Extract (11.25 mg 1 capsule, BID, 7-day Midazolam (15 mg) ↑ AUC and Cmax ; ↓ 52% in ↓ CYP3A [110]
deoxyschizandrin per CL/F
capsule)
Hibiscus sabdariffa Aqueous extract (NA) 300 ml Simvastatin (40 mg) ↑ 44.6% in CL/F; ↓ 18% in NA [111]
Cmax and 30.8% in AUC
300 ml, QD, 2-day Diclofenac (25 mg) ↓ Excretion [112]
1 000 ml Zobo drink Acetaminophen (1 g) ↑ CL/F [113]
300 ml Karkadi (Sudanese Chloroquine (600 mg) ↓ AUC and Cmax [114]
beverage)
Moringa oleifera Leaf suspension (NA) 3 g, QD, 7-day Amodiaquine ↓ Cmax May relate to [115]
(10 mg/kg) CYP2C8
Notes: a ↑, ↓, =: “increase,” “decrease,” and “no significant effect,” respectively; b ↑ and ↓: “induce” and “inhibit,” respectively; NA: not available.
several therapeutic drugs. Due to the potential induc- drugs by St John’s Wort were found to be mainly related
tion of CYP3A4 activity by garlic, the plasma AUC and to its potential induction of CYP3A4. A 14-day course of
Cmax of coadministered saquinavir decreased by 51 St John’s Wort administration caused twofold decrease
and 54%, respectively [77]. However, no alteration of in the plasma concentrations and AUC of alprazolam
warfarin pharmacokinetics by its coadministered garlic (substrate of CYP3A4) and also twofold increase in
tablet was observed [78]. alprazolam clearance [62]. Since CYP3A4 substrates
account for at least 50% of all currently marketed drugs,
caution should be made with the concomitant intake of
26.3.2 Pepper
St John’s Wort with therapeutic drugs that are substrates
Piperine is an alkaloid naturally occurred in plants of CYP3A4.
such as black pepper and long pepper. Black pepper has In addition to the effects on CYP3A4, the influence
been used in the traditional Chinese medicinal practice of St John’s Wort on P-gp was also suggested to be
to treat seizure disorders, and its active ingredient, responsible for the altered oral bioavailability of various
piperine, exhibited various beneficial effects including drugs. Two-week treatment with St John’s Wort extract
anticarcinogenic and anti-inflammatory activities. Sev- to healthy volunteers resulted in 1.5-fold increased
eral studies demonstrated that concomitant ingestion expressions of duodenal P-gp and CYP3A4 in both intes-
of piperine conferred potential alterations of bioavail- tine and liver and a subsequent 18% decrease in oral
abilities of various drugs. In a crossover clinical study, bioavailability of coadministered digoxin, the substrate
six healthy subjects in each group received a single oral of both P-gp and CYP3A4 [83]. Similarly, increased P-gp
dose of propranolol or theophylline alone or in combi- expression in human duodenal mucosa was found after
nation with piperine daily for seven days. The resultant 12-day treatment of St John’s Wort, which could lead to
shorter T max as well as higher Cmax and AUC were 25% reduction on the oral bioavailability of talinolol, a
observed in the subjects who received both piperine non-CYP3A4 metabolizable P-gp substrate [85].
and propranolol. Similarly, higher Cmax and AUC values
and a longer elimination half-life of theophylline were 26.3.4 Ginkgo Biloba
found with coadministration of piperine with theo-
Ginkgo biloba, originating from ancient China, has
phylline. Since propranolol and theophylline are mainly
been widely used for memory improvement in the
metabolized by CYP1A1 and CYP1A2, the enhanced
world. Several clinical studies demonstrated the
bioavailability of both propranolol and theophylline
induction of cytochrome P450 enzymes including
were suggested to be due to the potential inhibition of
CYP2C19 and 3A by ginkgo biloba. Pretreatment of
CYP1A1/2 by piperine [79]. In addition, the influence
ginkgo biloba extract for 12 days would increase the
of piperine on P-gp transporter was also suggested in
CYP2C19-mediated metabolism of omeprazole to its
some studies. Treatment with piperine in rodents and
metabolite 5-hydroxyomeprazole, which was more sig-
human resulted in increased plasma concentrations
nificant in CYP2C19 poor metabolizers [86]. Similarly,
of phenytoin, the substrates of P-gp, indicating the
a four-week treatment with ginkgo biloba decreased
inhibition of P-gp by piperine [80]. Series of clinical
the AUC and Cmax of midazolam (probe of CYP3A) by
HDI studies using probe drug cocktails from Gurley
34% and 31%, respectively in 14 healthy volunteers [87].
et al. demonstrated no inhibition on CYP3A or 2D6 by
Besides inducing the CYPs, Ginkgo Biloba was found
pepper [60, 61].
to be able to increase AUC and Cmax of Talinolol via
inhibition of P-gp [88].
26.3.3 St John’s Wort
As a popular herbal dietary supplement for the
26.3.5 Curcumin and Curcuma Rhizomes
Extract
treatment of depression, St John’s Wort was also a
well-known inducer for both CYP and P-gp. Its con- Curcuma rhizomes extract with curcumin as the major
comitant administration with cyclosporine was reported component is a mixture predominantly composed of
to lead to a potential risk of transplant rejection in kid- turmeric root extract and other spices such as coriander
ney transplant patients due to a 47% reduction in and fenugreek. It has been shown to possess activity
systemic cyclosporine concentration [81]. In addition, in the treatment and prevention of cancer, multiple
St John’s Wort was also found to reduce the AUC of sclerosis, and Alzheimer’s disease. A study in healthy
HIV-1 protease inhibitor indinavir by approximately volunteers suggested an upregulation of P-gp by cur-
57% [82]. Such decreased oral bioavailabilites of various cumin based on the observed evidence of the decreased
26.4 Summary 517
Cmax and AUC values of coadministered talinolol, a 26.3.8 Vitamins

P-gp substrate [90].
Unlike the often-reported pharmacokinetics-based
DDCIs for above-mentioned dietary supplements,
26.3.6 Grapefruit Juice pharmacodynamics-based interactions are commonly
Since 1990s, extensive reports on the potential inter- reported for vitamins. Coadministered vitamin C and
actions between flavonoids containing grapefruit juice vitamin E could improve fasting blood sugar and
and various coadministered drugs have stimulated decrease the production of glutathione [99], whereas
remarkable interest in the studies of dietary flavonoids. coadministration of folic acid and enalapril could lead
Grapefruit juice was reported to increase oral bioavail- to the development of proteinuria in diabetic patients
ability of cyclosporine by 45% and decrease the Cmax with hypertension [101].
and AUC of its metabolite by 21% and 15%, respectively
[92]. Further studies on grapefruit juice consistently
indicated that it could markedly improve oral bioavail- 26.4 Summary
ability of CYP3A4 substrates including felodipine [96],
terfenadine [93], and midazolam [94]. It was speculated Knowledges on both DDIs and DDCIs are highly
that such inhibitory effects on CYP3A4 and/or P-gp by important to ensure the safety and efficacy of multiple
grapefruit juice might be responsible for the reported drug therapy. DDIs mainly occurred during intesti-
increased oral bioavailability of various drugs, which nal absorption, hepatic metabolism, kidney-mediated
are CYP3A4 and/or P-gp substrates. In grapefruit juice elimination, and tissue distribution with intestinal
takers, there was about 20% increase in the AUC of pH, mobility, CYPs, and transporters in both intestine
diltiazem, the substrate of both CYP3A4 and P-gp [95]. and liver as the key factors. With the recent research and
It was suggested that flavonoids, including naringin, development, intestinal microbiota-mediated DDIs and
naringenin, quercetin, and kaempferol, were the active drug–biologics interactions set the future research direc-
ingredients in grapefruit juice responsible for the inhi- tions for DDI. Comparing with DDIs, clinical evidenced
bition of intestinal CYP3A4 activity and could lead to studies on DDCIs and related mechanisms remain
the increased oral bioavailabilities of coadministered insufficient, which are mainly due to the complexity
drugs, which are CYP3A4 substrates [117]. of the compositions of dietary chemicals, inconsis-
tent quality of the dietary products, and the lack of
well-designed clinical trials. Further mechanistic stud-
26.3.7 Caffeine ies on dietary chemicals and dietary supplements with
Caffeine could be coadministered with Cisplatin and known active ingredients and compositions are needed
Doxorubicin for the chemotherapy medication. The for better understanding of the risk, incidence, and
response rates of radiographic and histological indi- mechanisms of drug–dietary chemical interactions so
cated that caffeine-participated chemotherapy could be as to accurately predicate their potential outcomes in
beneficial to the survival of cancer patients [97]. the drug therapy.
Abbreviations
DDIs drug–drug interactions MRP2 multidrug resistance protein 2
DDCIs drug–dietary chemical interactions P-gp P-glycoprotein
GI gastrointestinal OCT organic cation transporter
AUC area under the curve OAT organic anion transporter
CYP cytochrome P450 BCRP breast cancer resistance protein
UGT uridine diphosphate glucuronosyl BESEP bile salt export pump
transferases MATE multidrug and toxic compound extrusion
SULT sulfotransferases mAbs monoclonal antibodies
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Drug–Drug Interactions and Drug–Dietary Chemical Interactions

26.1 Introduction 26.2 Drug–Drug Interactions (DDIs)

I. Absorption III. Distribution and Elimination

PEPT1 ASBT MRP2 P-gp OATP2B1 Apical

Alteration of pH ↑ Gastric pH Cefpodoxime H2 Receptor ↓ 30 – 40% in F [2]

Table 26.1 (Continued)

↑ P-gp Ranitidine Rifampicin ↓ 53% and 52% in [22]

Table 26.1 (Continued)

Nebivolol Paroxetine ↑ 510% in AUC [35]

26.2.1.2 Formation of Insoluble Complex in GI Tract and hydroxy-methylglutaryl coenzyme A reductase

Dietary Substance Dose and Victim drug (dose Effect of Potential

Dietary Substance Dose and Victim drug (dose Effect of Potential

Dietary Substance Dose and Victim drug (dose Effect of Potential

Cmax and AUC values of coadministered talinolol, a 26.3.8 Vitamins

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