Hepatic Elimination

Pharmacokinetics

Presented By: Gina Archer

Indira Fawkes
Onyx Flowers
Stephen Kemp
Maria Major
Lakeisha Moncur
Jerome Nugent
Nakita Storr
The Liver: Anatomy

 located in the upper right-hand portion of

the abdominal cavity beneath the
diaphragm

 Oxygenated blood flows in from the

hepatic artery

 Nutrient-rich blood flows in from the

hepatic portal vein

 Lobes lobules small ducts

larger ducts hepatic duct.

 The hepatic duct transports bile to the

gallbladder and duodenum
 The Liver: Function &
Diseases
 production of bile, cholesterol  Wilson's Disease
and special proteins to help
carry fats through the body.  Hepatitis
 conversion of excess glucose
into glycogen.  Liver cancer
(hepatocellular
 regulation of blood levels of
carcinoma)
amino acids.
 conversion of poisonous  Cirrhosis
ammonia to urea.
 clearing the blood of drugs  Hemochromatosis
and other poisonous
substances.
 regulating blood clotting.
 resisting infections.
Phase 1 Metabolism

HYDROLYSES REDUCTION
OXIDATION
Oxidation
– Formation of new polar functional groups

– Example:

-Addition of oxygen onto the phenyl of

phenylbutazone to form oxyphenbutazone (more

polar active metabolite). RH ROH

Hydrolysis

– Involves unmasking existing polar groups.

– Or breaking an existing ester or amide bond

– Example: Aspirin - Salicylate

Reduction
– The interchanging of existing functional groups.
• Example:
-It converts the azo-linkages (N=N)
bond to amines.
Sulphasalazine  sulfapyridine + 5-aminosalicylic acid

IMPORTANCE OF PHASE ONE REACTIONS

1. To enhance excretion

2. Prepare for phase two metabolism.

Drug Metabolism- Phase 2
• Involves the addition of molecules naturally found in the
body (conjugation).

• Conjugating agents: Acetyl-CoA, Glucuronic acid,

Glutathione, Methyl, Sulfate & Glycine.

• Conjugation improves water solubility

– Aids in better excretion of drugs
– Decrease drug pharmacological activity
Types of Conjugation
A. Glucuronidation- the attachment of glucuronic acid
to drug molecules.
A. e.g. Acetaminophen
B. Sulfation- the attachment of sulfate group to drug
molecules
A. e.g. Phenols (Albuterol)
C. Methylation-the attachment of methyl group to drug
molecules.
A. e.g. Norepinephine Epinephrine
D. Amino acid conjugation- the attachment of glycine
to drug molecules
A. e.g Brompheniramine
E. Acetylation- the attachment of acetyl group to drug
molecules.
A. e.g Cilastatin
F. Glutathione conjugation-the attachment of
glutathione group to drug molecules
A. e.g. Azathioprine
Hepatic Clearance

Types of Clearance
• Unbound Intrinsic Hepatic Clearance (CLunit ): The liver’s
ability to remove a drug from the body without the
influence of blood flow or protein binding. Clunit is a
function of enzyme activity or biliary excretion
• Restrictive clearance: Hepatic of a drug is depended on
protein binding and enzyme activity, only the unbound
drug is eliminated with each pass through the liver. Eg.
Diazepam and warfarin.
• Non-restrictive clearance: Rapid metabolism by the liver
that protein binding does not significantly affect
elimination. E.g Propranolol.
• Systemic Clearance: Measure of the efficiency with which
a drug is irreversible removed from the body.
Models Used in Hepatic
Clearance
• Venous equilibrium: Model predicts changes in drug
concentration as a function of blood flow, protein binding,
and enzyme activity. The model assumes that blood exiting
the liver in the hepatic vein is in equilibrium with the blood
that is bathing the sinusoids in the liver.
Hepatic metabolizing
enzyme systems
 Can metabolize a seemingly endless array of drug
substrates

 the newer fully synthetic drugs that have no close

structural counterparts in nature are successfully
metabolized by the liver and irreversibly removed or
‘cleared’ from the body

 liver hepatocytes contain all the necessary enzymes for

the metabolism of drugs.

 main enzymes involved in metabolism belong to the

cytochrome P450 group

 housed in the smooth endoplasmic reticulum of the cell

Phase I metabolism
• Cytochrome P450 enzymes are the predominant
catalysts of phase I metabolism in the liver.
• The P450 enzymes are said to function as mono-
oxygenases that insert one atom of oxygen into the
substrate molecule.
• Cytochrome P450s comprise a gene super family of
heme-thiolate proteins with 57 members in the human
genome.
Absorbance spectrum, 400-500 nm
(CO difference spectra), of
cytochrome P450
Hepatic metabolizing
enzyme systems
• A subset of approximately 15 P450 enzymes belonging
to the CYP1, 2 and 3 gene families mediates 70–80% of
all phase I-dependent metabolism of therapeutic drugs
and participates in the metabolism of countless other
xenobiotic chemicals.
Major human drug-metabolizing cytochrome
P450s and receptors responsible for inductive
regulation

Cytochrome P450 family Member Regulating receptor

CYP1 CYP1A1 AhR
CYP1A2 AhR
CYP2 CYP2A6 CAR
CYP2A13
CYP2B6 CAR, PXR
CYP2C8 PXR
CYP2C9 CAR, PXR
CYP2C18
CYP2C19 PXR, CAR
CYP2D6
CYP2E1
CYP2F1
CYP2J2
CYP3 CYP3A4 PXR, CAR

CYP3A5 PXR, CAR

CYP3A7a PXR
 ROLE OF CYP ENZYMES IN HEPATIC
DRUG METABOLISM

RELATIVE HEPATIC CONTENT % DRUGS METABOLIZED

OF CYP ENZYMES BY CYP ENZYMES
CYP2E1
CYP2D6 7%
2%

CYP 2C19
11%
CYP 2C CYP 2C9
17% 14% CYP2D6
OTHER 23%
36%
CYP 1A2 CYP 1A2
12% 14%

CYP 3A4-5 CYP2E1

26% CYP 3A4-5
5%
33%
Structure of cytochrome P450
Phase II metabolism
enzyme systems
 collectively known as ‘transferases’

 Most transferases also belong to gene families with

individual members catalysing the conjugation of a
distinct but often overlapping range of substrates.
Table 2: Some major human phase II drug-metabolizing
enzymes and receptors implicated in regulation.
Superfamily Function Substrate examples Gene Receptors implicated
familiesa in regulation
Glutathione S- Catalyse Adriamycin, BCNU, GSTAc GSTA2, CAR, PXR,
transferases nucleophilic busulfan, AhR
(GST) attack by GSH on carmustine, chlorambucil,
non-polar cyclophosphamide, DDT,
compounds inorganic arsenic, pesticides
GSTM
GSTP
GSTS
GSTT1
GSTZ
GSTO
Sulphotransferases Sulphation Steroid hormones, bile acids, SULT1 SULT1A1, CAR
(SULT) isoflavones, paracetamol,
Minoxidil
SULT2 SULT2A1, VDR
SULT4
N-acetyltransferases N-acetylation, Arylamines NAT1
(NAT)
O-acetylation N-hydroxylated NAT2
heterocyclic amines
UDP- Glucuronidation Bilirubin, paracetamol, UGT1A UGT1A1, PXR,
glucuronosyltransferases morphine, CAR,
(UGT)
zidovudine, NSAIDs UGT2B UGT1A6 HNF1a
UGT2B4 AhR,
SHP
UGT2B7 FXR, ?
PPAR
HNF1a
What is Enzyme Induction?
• Enzyme induction is a drug- or chemical-stimulated
increase in enzyme activity, usually due to an increase in
the amount of enzyme present. – (Shargel et al 2005)

• Can be caused by exposure to drugs, pesticides,

polycyclic aromatic hydrocarbons, and environmental
xenobiotics
Factors Affecting
Drug Therapy

Phenobarbital vs
Warfarin
• Induction of
microsomal enzymes
CYP3A1 & CYP2B2 by
Phenobarbital
increases the
metabolism of
warfarin and,
consequently
decreases the
anticoagulant effect.
 Factors Affecting Drug
Therapy
Oral Contraceptive Steroids UNEXPECTED
Rifampin PREGNANCY

INDUCTION

CYP3A4

Inactive & Excreted

CONSEQUENCE
 Factors Affecting Drug
Therapy
• Cigarette smoke contains
minute amounts of polycyclic
aromatic hydrocarbons, such as
benzo[α]pyrene, which are
potent inducers of microsomal
cytochrome P-450 enzymes
• Theophylline is metabolized
more rapidly in smokers than in
nonsmokers. So smokers wont
experience benefits of
theophylline as much as
nonsmokers.
• Enzyme induction also may
affect toxicity of some drugs
by enhancing the metabolic
formation of chemically
reactive metabolites!!!

• Example: oxidation of
acetaminophen by alcohol
 Factors Affecting Drug Therapy
Acetaminophen
Alcohol

INDUCTIO
N
CYP2E
1
p-Quinone Imine
(TOXIC!)

CONSEQUENCE
Inhibitors and how they
affect drug therapy
• Many drugs may increase or decrease the activity of
various CYP isozymes either by inducing the
biosynthesis of an isozyme (enzyme induction) or by
directly inhibiting the activity of the CYP (enzyme
inhibition).
• This is a major source of adverse drug interactions,
since changes in CYP enzyme activity may affect the
metabolism and clearance of various drugs. For
example, if one drug inhibits the CYP-mediated
metabolism of another drug, the second drug may
accumulate within the body to toxic levels.
Importance of drug interactions

Drug interactions are especially important to take

into account when using drugs of
• vital importance
• those with a narrow therapeutic index
• Especially when given to elderly or persons with
reduce hepatic function.
 Naturally occurring compounds may also induce or inhibit
CYP activity

• Saint-John's wort, a common herbal remedy induces

CYP3A4, but also inhibits CYP1A1, CYP1B1, CYP2D6, and
CYP3A4 

• Tobacco smoking induces CYP1A2 (example CYP1A2

substrates are clonazapine, olanazapine, and fluvoxamine) .

• Starfruit juice has also been shown to inhibit CYP2A6 and

other CYPs.

• Watercress is also a known inhibitor of the Cytochrome

P450 CYP2E1, which may result in altered drug metabolism
for individuals on certain medications (ex., chlorzoxazone).
Hepatic Elimination
Pediatric Elderly
 Infants don’t develop an  Renal function decreases
enzyme system until > 2 which leads to a decrease
weeks after birth in elimination of renal
 Decrease in plasma protein excreted drugs
concentration leads to a
decrease in plasma protein  Serum albumin decreases
binding decreased. which leas to a decrease
 Decrease in affinity of in protein binding
protein for drug binding.
 A decrease in GI pancreatic
enzyme concentration
affects absorption of fat
soluble drugs.
 Hepatic Elimination:
Pediatric & the Elderly

 Age related decreases in liver mass, hepatic blood

flow & hepatic enzyme activity in the elderly
 Metabolic capacity of liver is decreased also.

 Inter individual variability in age & disease results

in dose adjustment for some drugs.
 Benzodiazepines, such as diazepam and
flurazepam tend to accumulate .