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Molecular Pharmacokinetics of Catharanthus (Vinca) Alkaloids

Dominique Levêque and François Jehl
J. Clin. Pharmacol. 2007; 47; 579
DOI: 10.1177/0091270007299430

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 Molecular Pharmacokinetics of Catharanthus
(Vinca) Alkaloids
Dominique Levêque, PharmD, PhD, and François Jehl, PharmD, PhD
This review focuses on the published data regarding the
molecular determinants (enzymes, transporters, orphan
nuclear receptors) of Catharanthus (vinca) alkaloids phar-
macokinetics in humans. The clinical impact of these
determinants (drug disposition, drug-drug interactions) is
also discussed.
C atharanthus (also called vinca) alkaloids consti-
tute a class of anticancer drugs that currently
includes vinblastine, vincristine, vindesine, and
vinorelbine. These are dimeric molecules formed by
the catharanthine unit and the vindoline unit.
Vinblastine and vincristine were originally isolated
from extracts of the ornamental plant Catharanthus
roseus (L) G Don, erroneously referred to as Vinca
rosea.1,2 They have been used clinically since the
end of the 1950s but still remain major drugs in the
treatment of acute lymphoblastic leukemia, non-
Hodgkin lymphomas, myeloma, and Hodgkin lym-
phoma. In addition, contrasting with most of the
recent anticancer agents, including the so-called tar-
geted therapies, vinblastine and vincristine are often
given in a curative intent. Vindesine (deacetylvin-
blastine amide)3 and vinorelbine (nor-5′-anhydrov-
inblastine)4 are semisynthetic compounds that were
developed in the 1970s but were later shown not
to gain in therapeutic activity. Vindesine is not
approved in the United States, and in France, it is
predominantly used in combination, in the treat-
ment of aggressive forms of non-Hodgkin lym-
phomas. Vinorelbine is most exclusively given in a
From the Pharmacy, Hôpital Hautepierre, Strasbourg, France, and the
Institute of Bacteriology, Strasbourg, France. Submitted for publication
September 4, 2006; revised version accepted January 7, 2007. Address
for correspondence: Dominique Levêque, Pharmacy-Pharmacology,
Hôpital Hautepierre, Avenue Molière, 67000 Strasbourg, France; e-mail:
dominique.leveque@chru-strasbourg.fr.
DOI: 10.1177/0091270007299430
J Clin Pharmacol 2007;47:579-588
Keywords: Catharanthus alkaloids; vinblastine; vincristine;
vindesine; vinorelbine; CYP450; drug trans-
porters; orphan nuclear receptors; drug-drug
interactions
Journal of Clinical Pharmacology, 2007;47:579-588
©2007 the American College of Clinical Pharmacology
palliative intent, in the treatment of advanced non-
small-cell lung cancer, advanced breast cancer, and
refractory lymphoid malignancies (off-label indica-
tion). Vinorelbine therapeutic impact is greater when
given as adjuvant (or postoperative) treatment asso-
ciated with cisplatin in certain patients with resected
non-small-cell lung cancer.5,6 Vinflunine, a fluori-
nated derivative of vinorelbine, is currently in clini-
cal development.7,8
Catharanthus alkaloids inhibit cell proliferation
during mitosis after binding to the microtubules,
the major components of the mitotic spindle.9
The microtubules are dynamic polymers composed
of alpha and beta tubulin heterodimers. The molec-
ular mechanism by which Catharanthus alkaloids
exert their cytotoxic effect was reevaluated 15 years
ago. Initially, and based on experiments performed in
the micromolar range, it was thought that Catharanthus
alkaloids were microtubule depolymerizing agents.
In fact, they act at low doses (in the nanomolar
range) without affecting the microtubule polymer
mass. Hence, the antiproliferative activities of
Catharanthus alkaloids are related to the inhibition
of microtubule dynamics, which leads to mitotic
block and apoptosis.9
Contrasting with other anticancer drugs, the clin-
ical pharmacokinetics of Catharanthus alkaloids
have not raised great interest, probably imputable to
analytical difficulties inherent to the low doses
administered. In addition, very few pharmacoki-
netic drug-drug interactions have been identified or
prospectively explored, and the knowledge about
579
 LEVÊQUE AND JEHL
the molecular kinetic determinants (enzymes, trans-
porters, orphan nuclear receptors) appears limited.
The aim of this article is to review what is known
about the molecular pharmacokinetics of Catharan-
thus alkaloids in humans, based on the published
literature (excluding animal data).
CLINICAL PHARMACOKINETICS OF
CATHARANTHUS ALKALOIDS
The pharmacokinetics of Catharanthus alkaloids have
been the subject of some comprehensive reviews.10-13
Regarding the kinetic parameters, the values are
heterogeneous partly depending on the analytical
methodology (radioassay, radioimmunoassay, liquid
chromatography) and the duration of the studies.
Catharanthus alkaloids are most commonly adminis-
tered by short intravenous injection (1-15 minutes), on
a weekly basis, or more rarely by continuous infusion
(vincristine in the treatment of myeloma or mantle cell
lymphoma). Vinorelbine is the sole Catharanthus alka-
loid available in an oral form (soft capsule), given as a
single dose once weekly.
Overall, administered intravenously in adults, their
kinetic profiles are characterized by a long terminal
half-life (24-48 hours), a clearance ranging from 300 to
1400 mL/min with a weak urinary elimination, an
important volume of distribution (620-5250 L) reflect-
ing in part their lipophilicity, and a wide tissue diffu-
sion (Table I). The serum concentration peaks (Cmax)
after intravenous injection are around (vinorelbine) or
less than 1 µM (vinblastine, vincristine, vindesine).
Tissue concentrations are much higher than those in
serum, as it has been demonstrated with vinorelbine
in lung tissue (up to 300-fold).13 The bioavailability of
oral vinorelbine is around 40%.13
HUMAN MOLECULAR DETERMINANTS OF
CATHARANTHUS ALKALOIDS
PHARMACOKINETICS
Enzymes
Little data are available on the metabolic elimination
of Catharanthus alkaloids in humans. It is assumed
that Catharanthus alkaloids are cleared by the liver,
but the importance of biotransformation remains
largely unknown. Although numerous types of bio-
transformation appear possible,14 to date, only 2 major
metabolites (desacetylvinblastine and desacetylvi-
norelbine), the structures of which have been con-
firmed by mass spectrometry, have been identified in
580 • J Clin Pharmacol 2007;47:579-588
human biological fluids.10,15-17 Paradoxically, these
metabolites have not been found in the in vitro bio-
transformation experiments. Desacetylvinblastine has
been detected in the urine and stool of a patient who
received radioactive vinblastine.15 This metabolite
was found in very low amounts, representing less than
1% of total dose in both excreta. The structure of the
metabolite was confirmed later. Likewise, desacetylvi-
norelbine, the major metabolite of vinorelbine, has
been found in the urine of treated patients but in low
amounts, only representing 0.25% of the injected
dose.16 In addition, data from an abstract form reported
the detection of desacetylvinorelbine in blood and bile
samples of 1 patient.17 Besides desacetylvinorelbine,
12 other minor metabolites, including 3-6-epoxyvi-
norelbine, were characterized in biological samples
(blood, urine, bile) of this patient, using mass spec-
trometry.17 The biotransformation of vindesine18 and
recently (2006) vincristine19 has been reported in vitro
(see below), but no metabolite has been detected in
human biological fluids.
The implication of enzymes involved in the metab-
olism of Catharanthus alkaloids has been explored in
vitro at clinically relevant plasma concentrations in
most experiments. The isoenzyme cytochrome (CYP)
P450 3A4 contributes to the biotransformation of vin-
blastine, vindesine, and vinorelbine in human liver
microsomes. Incubation of tritiated vinblastine (1
µM)20 or tritiated vindesine (1 µM)18 with human liver
microsomes primarily leads to the formation of an
apparently less polar compound of unknown struc-
ture, based on a radioactive detection. Regarding vin-
blastine, the presence of desacetyl metabolite was not
reported.20 Metabolism of both alkaloids was inhib-
ited by anti-CYP3A polyclonal antibodies as well as by
ketoconazole (vinblastine), cyclosporine, and nifedip-
ine (vindesine). In addition, vinblastine and vindesine
metabolism was shown to correlate with CYP3A
activity in a bank of 39 human liver microsomes.18,20
Two articles have reported the identification of the
CYP involved in the in vitro metabolism of vinorel-
bine.21,22 Kajita et al21 first observed additional chro-
matographical peaks corresponding to polar metabolites
of unknown structure after the incubation of vinorel-
bine (0.5 µM) using human liver microsomes and
recombinant CYP3A4. Desacetylvinorelbine, the major
in vivo metabolite, was not found. Antihuman
CYP3A4/A5 antibodies, troleandomycine, keto-
conazole, itraconazole, and fluconazole signifi-
cantly reduced vinorelbine metabolism in human
liver microsomes. Vinorelbine metabolism was also
shown to be catalyzed by CYP3A5 in a recombinant
expression system. Other isoenzymes—CYP1A1,
 MOLECULAR PHARMACOKINETICS OF CATHARANTHUS (VINCA) ALKALOIDS
Table I Pharmacokinetic Parameters for Intravenous Catharanthus Alkaloids in Adults10-13
Molecular Usual Dose
Weight (Intravenous Major
Drug (Base) Injection), mg/m2 Metabolites
Vinblastine 811 4-7 Desacetylvinblastine
(urine, stool)
Vincristine 825 1.4 NR
Vindesine 754 2-4 NR
Vinorelbine 779 25-30 Desacetylvinorelbine
(blood, urine, bile)
Vd, volume of distribution; CL, clearance; t1/2, terminal half-life; NR, not reported.
CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9,
CYP2C19, CYP2D6, and CYP2E1—were not involved
in the biotransformation. In the second article, the dis-
appearance of high-concentration vinorelbine (128
µM) ranged from 2% to 35% after incubation with
human liver microsomes.22 The chromatogram of 1
incubate showed additional peaks corresponding to
apparently more polar compounds of unknown struc-
ture. The search for desacetylvinorelbine was not
mentioned. A relation was reported between vinorel-
bine disappearance and CYP3A activity. Vinorelbine
biotransformation was reduced in the presence of anti-
CYP3A polyclonal antibodies, ketoconazole, and
troleandomycine.22
For a long time, vincristine has been suspected to
be metabolized via CYP3A4 because it had an
inhibitory effect (at a very high concentration, 35 or
100 µM) on in vitro vinblastine and vindesine
metabolism.18,20 Nevertheless, a CYP inhibitor is not
necessarily a substrate for this same CYP. In fact,
vincristine metabolism was only established in 2006
(45 years after its introduction in the clinic) in vitro,
using human recombinant CYP enzymes.19 The bio-
transformation of the alkaloid (5 µM) was primarily
catalyzed by CYP3A4 and CYP3A5 and led to
metabolites called M1, M2, and M4. The formation
of M1, the major metabolite whose structure corre-
sponds to the opening of the piperidine ring of the
catharanthine moiety, was more efficient with
CYP3A5 (9- to 14-fold higher intrinsic clearance).
Incubation with CYP1A1, CYP1A2, CYP2A6, CYP2B6,
CYP2C8, CYP2C9, CYP2D6, and CYP2E1 did not
show a significant disappearance of the parent drug
(ie, less than 10% substrate loss).19
Regarding conjugation reactions, neither sulfate
nor glucuronide of vinblastine has been found in the
urine of a patient.15 The search for a glucuronide of
vinorelbine in human urine has been performed
unsuccessfully.23 In addition, no conjugate has been
DRUG METABOLISM/TRANSPORT
% of the Vd (L) CL (mL/min)
Dose as Calculated Calculated
Metabolites for 70 kg for 70 kg t1/2,h
<1% in urine 1900 840 24
and stool
NR 1680 750 22
NR 620 300 24
0.25% in urine 5250 1470 42
observed in the bile, blood, and urine of a patient
who had received intravenous vinorelbine.17
In summary, vinblastine, vindesine, and vinorel-
bine are metabolized in vitro via CYP3A4. The struc-
ture of the in vitro metabolites is not elucidated. The
metabolism of vincristine is now demonstrated in
vitro and involves CYP3A5 and CYP3A4. The struc-
ture of the metabolites is known.
Drug Transporters
Transporters are transmembrane proteins involved
in the diffusion of drugs across cell membranes
(uptake/efflux). They are distributed in 2 major
superfamilies, the solute carrier (SLC) transporters
(uptake and efflux) and the adenosine triphosphate
(ATP) binding cassette (ABC) transporters (efflux).24
Currently, Catharanthus alkaloids are only concerned
with ABC transporters that require ATP hydrolysis for
drug cell efflux. Their identifications mostly derive
from studies on cellular drug resistance to anticancer
agents as they were first described as efflux pro-
teins lowering intracellular concentrations. Thus,
Catharanthus alkaloids have been the subject of
numerous studies, although the interest of these
transporters as pharmacokinetic determinants (ie,
their role in healthy tissues) was found afterward.
P-glycoprotein
P-glycoprotein (P-gp or ABCB1), the most studied
drug transporter, was discovered in 1976,25 and its
membrane expression was later shown (1983) to pos-
itively correlate with resistance to vinblastine and
vincristine.26 In 1986, Cornwell et al27 demonstrated
the binding of a photoaffinity analog of vinblastine
on P-gp, and the same year, the role of P-gp as a trans-
porter was proposed.28 Transport of vinblastine was
shown using plasma membrane vesicles from cancer
cells expressing P-gp.29 The identification of P-gp in
581
 LEVÊQUE AND JEHL
normal tissues, particularly in organs involved in the
disposition of drugs, was considered of interest as a
pharmacokinetic determinant. P-gp potentially limits
the oral absorption and diffusion in the brain and
mediates renal and biliary excretions.30,31 Using canine
renal cells expressing human P-gp, Horio et al32 first
demonstrated active transport of vinblastine and vin-
cristine at the luminal (apical) side. The pharmaco-
kinetic significance of this finding is limited given
the low renal elimination of the Catharanthus alka-
loids. Resistance to vindesine has been associated
with overexpression of P-gp in vitro.33 A photoaffin-
ity analog of vindesine has been shown to bind to
P-gp,34 but no formal transport has been demon-
strated. Information regarding vinorelbine and P-gp
is scarce. As its congeners, cellular resistance has
been associated with expression of P-gp,33,35 but it is
not known if vinorelbine is really transported by
P-gp. Particularly, the potential impact of P-gp on the
limited bioavailability of oral vinorelbine remains to
be explored. Overall, P-gp may mediate the biliary
excretion at the apical side of hepatocytes of vinblas-
tine and vincristine and may limit their distribution
in brain tissue.
Multidrug Resistance Proteins
The multidrug resistance protein (MRP) family is
currently composed of 9 transporters (MRP1 to
MRP9).36 As for P-gp, MRP (now MRP1 or ABCC1)
was first identified as a factor associated with a phe-
notype of multidrug resistance to certain anticancer
agents.37 In contrast to P-gp, MRP1 is expressed at
the basolateral side of enterocytes and kidney cells,
thus pumping drugs toward blood.38 The expression
of MRP1 in the liver is considered to be very low.38
MRP1 present in the endothelium of blood capillar-
ies (like P-gp) may limit the diffusion of drugs at the
blood-brain barrier. In all, the relevance of MRP1 to
clinical pharmacokinetics appears uncertain. The
expression of MRP1 in cancer cells has been associ-
ated with reduced accumulation and in vitro resis-
tance to vinblastine and vincristine.36 Vincristine is
transported by MRP1 with the requirement of glu-
tathion.39-42 Curiously, the transport of vinblastine by
MRP1 has not been established.43,44 The interaction
of vindesine and vinorelbine with MRP1 is not doc-
umented. Given the pharmacokinetic behavior of
vincristine, MRP1 (in addition with P-gp) may limit
its diffusion across the blood-brain barrier.
MRP2 (or ABCC2), previously referred to as the
canalicular multispecific organic anion transporter (c-
MOAT), was identified in the canalicular membrane of
hepatocytes as a determinant of bilirubin glucuronide
582 • J Clin Pharmacol 2007;47:579-588
and xenobiotics export into the bile.36 MRP2 is also
present at lower levels, at the apical side of enterocytes
and proximal renal cells.36,38 MRP2 was shown after-
ward to confer resistance to some anticancer drugs. In
vitro cellular resistance to vincristine has been associ-
ated with membrane expression of MRP2.45,46 The
transport of vinblastine but not vincristine has been
demonstrated.47-49 The interaction of vindesine and
vinorelbine with MRP2 has not been evaluated. In all,
MRP2 may mediate (in conjunction with P-gp) the bil-
iary excretion of vinblastine.
The transport capabilities of other isoforms of
MRP are currently unknown. Resistance to vin-
cristine is not mediated by MRP3, MRP4, MRP5,
MRP6, and MRP8 in vitro.50 Furthermore, expression
of MRP6 does not confer resistance to vinblastine.50
On the other hand, expression of MRP7 is associated
with resistance to vinblastine and vincristine.50 No
data are available regarding interactions of vindesine
and vinorelbine with MRP3 to MRP9.
Initially associated with a phenotype of resistance
to anticancer drugs, breast cancer resistance protein
(BCRP, also referred to as MXR or ABCG2) has been
shown to be expressed in healthy tissue and to medi-
ate the transport of drugs.51 Breast cancer resistance
protein is located at the apical side of enterocytes
and hepatocytes. The transporter is also present in
endothelial cells of brain capillaries but is not
detected in kidneys.51 Cells overexpressing BCRP
remain sensitive to vinblastine and vincristine in
vitro.52-54 In addition, cells that overexpress BCRP do
not show decreased accumulation to vinblastine.52
Thus, BCRP is not a pharmacokinetic determinant for
vinblastine and probably vincristine. No data are
available relative to vindesine and vinorelbine.
Orphan Nuclear Receptors
Orphan nuclear receptors such as pregnane X recep-
tor (PXR, or SXR or NR1I2) and constitutive
androstane receptor (CAR or NR1I3) are transcrip-
tional factors playing a major role in the increased
expression of enzymes or transporters and are asso-
ciated with induction.55-57 Hence, well-known induc-
ers such as rifampin and phenytoin are known to
interact with PXR and CAR.55,58 Induction of enzymes
or drug transporters by anticancer drugs (taxanes,
oxazaphosphorines) is a relatively recent finding.57,59,60
This suggests that some anticancer agents may
induce their own elimination or activation, may
decrease the concentrations of a coadministered
drug, and also may generate cellular resistance in
tumor tissue. Nevertheless, from a clinical point of
 MOLECULAR PHARMACOKINETICS OF CATHARANTHUS (VINCA) ALKALOIDS
view, the pharmacokinetic and pharmacodynamic
impact of these observations remains largely unknown.
It has to be stressed that these drugs (except the oral
form of cyclophosphamide) are rarely given on a
daily chronic basis, thus limiting the consequences
of induction (this process is considered to be time
and concentration dependent).
Vinblastine, administered by continuous infusion
on 3 days, has been shown to induce CYP3A4
expression in vivo (assessed by the 60% increase in
midazolam clearance in 6 patients) and in vitro.61
However, the induction does not seem to be medi-
ated via activation of the orphan nuclear receptor
PXR, suggesting a possible posttranscriptional process.
As seen before, the clinical impact appears very lim-
ited because vinblastine is mostly administered as a
single injection repeated weekly or every 2 weeks as
in Hodgkin lymphoma.
Vincristine (10 nM and 100 nM) induces the
expression of mRNA for MRP2 and MRP3 in cell lines
expressing high or low levels of PXR.62 Induction of
CYP3A or P-gp was moderate and was also observed
in cell lines expressing high or low levels of PXR.
Overall, the increased expression of transporters or
CYP3A by vincristine is complex and appears time,
cell line, and concentration dependent. As for vin-
blastine, PXR is not the major mediator of induction.
CLINICAL IMPLICATIONS
Known molecular determinants of Catharanthus
alkaloids kinetics are CYP3A4, CYP3A5, P-gp, MRP1,
and MRP2, based on in vitro experiments (Table II).
Their clinical contribution may be evaluated by the
influence of their activity or expression (sometimes
genetically determined) on the interindividual vari-
ability of kinetic parameters (although the sources
of variability are multiple) and by the analysis of
kinetic interactions with inducers or inhibitors.
Drug Disposition
As seen before, P-gp may be involved in the biliary
excretion of vincristine. P-gp expression, assessed
by the analysis of variants of its gene MDR1 (certain
genotypes are associated with low expression of the
transporter), was not shown to affect vincristine
pharmacokinetics in 52 children.63 This study sug-
gests that the large variability in vincristine clear-
ance (up to 30–fold) was not explained by certain
genotypes of MDR1 (P-gp expression as the protein
was not determined).
DRUG METABOLISM/TRANSPORT
Metabolism of vinorelbine is catalyzed in vitro by
CYP3A4 and CYP3A5. Biliary elimination might be
mediated by P-gp. The impact of CYP3A and biliary
P-gp on the pharmacokinetics of vinorelbine given
intravenously has been explored in 34 patients.64
Biliary P-gp activity, evaluated by hepatic technetium-
labeled sestamibi clearance, was shown to be related
to vinorelbine blood clearance (P = .01). Hence, the
variability in the expression of P-gp partially accounts
for the interindividual variability in vinorelbine blood
clearance. Regarding the gene level, variability of the
clearance was not associated with certain variants of
MDR1. Hepatic CYP3A activity, assessed by midazo-
lam clearance (given as a probe substrate), failed to
correlate with the elimination of the alkaloid. This
was also reported by Schott et al,65 who did not find a
relation between blood clearance and CYP3A activity,
evaluated by the erythromycin breath test in 13
patients. By contrast, using another CYP3A probe sub-
strate (dexamethasone), Puisset et al66 observed a sig-
nificant correlation between the plasma clearance of
the corticoid and the blood clearance of vinorelbine
administered intravenously to 20 patients. No associa-
tion was found between vinorelbine blood clearance
and CYP3A5 genotype (enzymatic activity is related to
the wild-type gene).64 In addition, 2 patients, who
were carriers of the CYP3A5 wild-type gene, did not
exhibit a higher blood clearance than those (n = 18)
with a genetic variant (little enzymatic activity).66 In
another study, zosuquidar, an investigational P-gp
modulator, was shown to decrease the clearance of
intravenous vinorelbine by 20% to 24% in 11 patients.67
If viewed in a different light, these findings could also
suggest that the hepatic biotransformation does not
represent a major pathway for the elimination of
vinorelbine. As suggested by Wu and Benet,68 block-
ade of hepatic canalicular P-gp by a specific inhibitor
such as zosuquidar would lead to increased liver
exposure and, in turn, to increased clearance in case of
extensive metabolism. In summary, although no for-
mal transport has been demonstrated in vitro, P-gp
may be involved in the disposition of vinorelbine, par-
ticularly in the biliary excretion. Contrary to in vitro
findings in experiments, CYP3A appears to play a
minor role in the elimination of vinorelbine.
Drug-Drug Interactions
Besides descriptive aspects, knowledge of molecular
kinetic determinants is important to anticipate or
explain drug-drug interactions. Drugs inhibiting or
increasing the expression of these determinants may
alter the pharmacokinetics of Catharanthus alkaloids.
583
 LEVÊQUE AND JEHL

Table II Interactions of Catharanthus Alkaloids With Major Human Molecular Pharmacokinetic

Determinants as Substrates (Enzymes, Transporters) or Activators (Nuclear Receptors)
Nuclear Receptors
Transporters
Enzymes PXR
P-gp MRP1 MRP2 BCRP (SXR, CAR
Drug CYP3A4 CYP3A5 CYP2D6 CYP2C8 CYP2C9 CYP2C19 CYP1A2 CYP2B6 (ABCB1) (ABCC1) (ABCC2) (ABCG2) NR1I2) (NR1I3)

Vinblastine Yes20 ND ND ND ND ND ND ND Yes32 ND Yes47-49 No52 Yes (weak)61 ND

Vincristine Yes19 Yes19 No19 No19 No19 No19 No19 No19 Yes32 Yes39-42 ND No52 ND ND
Vindesine Yes18 ND ND ND ND ND ND ND ND ND ND ND ND ND
Vinorelbine Yes21,22 Yes21 No21,22 No21,22 No21,22 No21,22 No21,22 No21,22 ND ND ND ND ND ND

P-gp, P-glycoprotein; MRP, multidrug resistance protein; BCRP, breast cancer resistance protein; PXR, pregnane X receptor; CAR, constitutive androstane
receptor; ND, not determined.

Table III Drug Interactions (Possible or Probable) Reported or Explored With Catharanthus Alkaloids in
Humans
Control Kinetic Pharmacokinetic
Drug Interacting Drug Group Clinical Effect Documentation Effect Reference

Vinblastine Cyclosporine No Yes (increased toxicity) No 70

Erythromycin and No Yes (increased toxicity) No 71
cyclosporine
Vincristine Itraconazole No Yes (increased toxicity) No 73-76
Carbamazepine, Yes Unknown Yes Yes (increased 72
phenytoin clearance)
Felodipine Yes No Yes Yes (increased 77
half-life)
Cyclosporine No Yes (increased toxicity) No 69
Izoniazid No Yes (increased toxicity) No 69
Vinorelbine Cisplatine Yes Yes (increased activity) Yes No 78
Itraconazole No Yes (increased toxicity) No 79
Zosuquidar Yes Unknown Yes Yes (decreased 67
(investigational) clearance)

Clinically, very few drug-drug interactions have been
reported (Table III), despite the involvement of CYP3A
in their in vitro metabolism. These interactions are
possible or probable, and some of them do not figure
in the official labelings.67,69-79 They mostly concern
vincristine and frequently do not include pharma-
cokinetic data. (Kinetic interactions have only been
explored with vincristine and vinorelbine.)
Severe toxicities of vincristine and vinorelbine have
been observed in patients who were coadministered
the antifungal triazole itraconazole as prophylactic
therapy.73-76,79 These clinical reports probably consti-
tute the most relevant interactions with Catharanthus
alkaloids. Itraconazole is a dual inhibitor of CYP3A4
and P-gp in vitro.80,81 Although no kinetic documenta-
tion is available for both alkaloids, the interactions
might involve the blockade of P-gp-mediated transport
or the CYP3A pathway elimination.
Increased clearance (+63%) of vincristine has
been shown in 8 patients who were receiving carba-
mazepine and 1 patient on phenytoin. 72 These
antiepileptics are sometimes given to patients with
brain tumors to prevent seizures. Carbamazepine
and phenytoin are weak inducers of CYP3A4.82 In
addition, carbamazepine has been shown to increase
MRP2 expression.83 The decreased exposure to vin-
cristine might be related to metabolism and/or bil-
iary transport induction.
Nifedipine, a calcium channel blocker used as a
resistance modulator, enhanced vincristine half-life
by 400% in 12 patients.77 Nifedipine is a weak
inhibitor of CYP3A,84 and regarding its ability to
inhibit P-gp drug transport, studies have reported
either a weak activity or the absence of effect.85,86
Therefore, the mechanism of interaction remains
uncertain.

584 • J Clin Pharmacol 2007;47:579-588

 MOLECULAR PHARMACOKINETICS OF CATHARANTHUS (VINCA) ALKALOIDS
Severe vincristine neurotoxicity has been observed
in patients who were coadministered cyclosporine
as a P-gp reversant.69 The immunosuppressant that
inhibits P-gp-mediated transport87 might delay the
biliary elimination of vincristine.
Isoniazid has been suspected to increase vin-
cristine neurologic side effects in a patient receiving
a polychemotherapy for Hodgkin lymphoma.69 In
the absence of kinetic documentation, this possible
interaction has been imputed to a metabolic inhibi-
tion. Recently, isoniazid was shown to be a noncom-
petitive CYP3A inhibitor, providing a basis for the
metabolic hypothesis.88 Cells expressing P-gp accu-
mulated less intracellular isoniazid, suggesting an
eventual transport.89 Nevertheless, the ability of the
anti-infective agent to inhibit P-gp function has not
been established.
Regarding vinblastine, 2 phase I studies have
described increased toxicities to the alkaloid when
administered with cyclosporine given as a resistance
modulator.70,71 Besides P-gp, cyclosporine has been
described as a MRP2 drug transport inhibitor in
vitro.90 Blockade of P-gp and MRP2 might affect vin-
blastine elimination. In 1 study, the macrolide and
CYP3A inhibitor erythromycin was associated with
cyclosporine to decrease its metabolism.71 The inter-
action was attributed to erythromycin because the
severity of toxicity was greater in 1 patient receiving
the macrolide alone than in the 2 patients without it.
Overall, directly or indirectly, erythromycin might
also decrease vinblastine elimination via metabolic
inhibition.
CONCLUSION
Currently, the molecular determinants of Catharan-
thus alkaloids pharmacokinetics are CYP3A4,
CYP3A5, P-gp, MRP1, and MRP2. Knowledge has
greatly evolved with the elucidation of the vin-
cristine metabolic profile. Their clinical contribution
(mostly CYP3A and P-gp) appears in the analysis of
some drug-drug interactions. However, no clinical
effect (increased toxicity) has been directly linked to
a pharmacokinetic mechanism. In the absence of
kinetic documentation, relevant clinical interactions
are suspected to be the consequence of metabolic or
drug transport inhibition or induction. Given the
context of use, interactions may be anticipated with
recent antifungal agents such as posaconazole and
voriconazole, which might increase the exposure
of Catharanthus alkaloids. Furthermore, the intro-
duction of a new type of anticancer drugs (kinase
inhibitors) may lead to an unrecognized risk of inter-
action. Indeed, these oral drugs are given chronically,
DRUG METABOLISM/TRANSPORT
and some of them (imatinib) have great potential in
altering pharmacokinetics due to their enzymatic and
transport-inhibiting properties. Although they are
mainly administered as a single agent, they may be
associated with chemotherapy, such as imatinib in
Philadelphia chromosome-positive acute lymphoblas-
tic leukemia.
Financial disclosure: None declared.
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