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Influence of Anticonvulsants on the Metabolism and Elimination of Irinotecan

Influence of Anticonvulsants on the Metabolism and Elimination of Irinotecan

ABSTRACT: The hepatic metabolism and biliary secretion of irinotecan (CPT-11, Camptosar) and metabolites is complex and involves cytochrome P450 isoenzymes, carboxylesterases, glucuronosyltransferase, and the ATP-dependent export pumps MRP-2 and MXR. Enzyme-inducing antiepileptic drugs (EIAEDs) such as phenytoin and carbamazepine are known to induce several of the metabolic pathways relevant to ininotecan’s elimination. The North American Brain Tumor Consortium phase I study is designed to determine the maximum tolerated dose and pharmacokinetics of irinotecan given every 3 weeks to patients who are receiving EIAEDs. The EIAEDs have altered both the pharmacokinetics and pharmacodynamics of irinotecan. Peak concentrations and the area under the plasma-time curves for both irinotecan and SN-38 were significantly decreased in patients receiving EIAEDs. The recommended phase II dose of irinotecan administered every 3 weeks is 750 mg/m² for patients who have been receiving stable doses of EIAEDs. [ONCOLOGY 16(Suppl 7):33-40, 2002]

Irinotecan (CPT-11,
Camptosar) is a semisynthetic, water-soluble camptothecin derivative approved
for the treatment of patients with colorectal cancer. Irinotecan is also
undergoing phase I/II clinical testing and has shown promising activity against
a wide variety of tumor types, including recurrent malignant gliomas. A phase II
trial conducted at Duke University in patients with recurrent high-grade glioma
receiving weekly irinotecan doses of 125 mg/m² reported a 15% objective response
rate.[1] Of note, the toxicity and plasma exposure to irinotecan and its potent
metabolite SN-38 appeared to be lower than that of a historical database
comprising colorectal cancer patients.

Intravenously administered irinotecan (molecular weight [MW]: 587) is
metabolized in the liver by cytochrome P450 3A4/5 (CYP 3A4/5) enzymes to the
less active oxidative metabolites APC—7-ethyl-10-[4-N-(5-aminopentanoic
acid)-1-piperi-dino]-carbonyloxycamptothecin (MW: 619)—and NPC—7-ethyl-10[4-(piperidino)-1
amino]carbonyl-oxycamptothecin (MW: 519).[2,3] Irinotecan is also bioactivated
in the liver by carboxylesterases (predominantly hCE2) to the potent
topoisomerase I inhibitor SN-38 (MW: 393)[4-6] (Figure

SN-38 is eliminated mainly through conjugation by hepatic uridine-diphosphoglucuronosyl
transferase (UGT-1A1) to SN-38 glucuronide (SN-38G)[7] (Figure
). SN-38G has
only 1/100 the antitumor activity of SN-38. UGT-1A1 is the same isoenzyme
responsible for glucuronidation of bilirubin.[8] Grade 4 toxicity
(neutropenia/diarrhea) has been reported in patients with deficient UGT-1A1
activity (Gilbert’s syndrome) after receiving irinotecan.[9] The relationship
of genetic polymorphism of UGT-1A1 and irinotecan toxicity was recently
reported.[10] Patients who are either homozygous or heterozygous for the
UGT-1A1*28 genotype are at risk for severe irinotecan-associated toxicity.

The canalicular multispecific organic anion transporter (MRP-2) reportedly is
responsible for the biliary transport of the carboxylate forms of irinotecan and
SN-38, as well as the lactone and carboxylate forms of SN-38G.[11] MRP-2 is
present in apical membranes of the liver, kidney, and intestine, and is
expressed in human lung, gastric, and colorectal cancer cells.[12] MRP-2
functions as a conjugate export pump mediating the unidirectional transport of
bilirubin glucuronides, reduced folate and amphiphilic anions, particularly
lipophilic substances conjugated with glutathione, glucuronide or sulfide.[13]
In the rat, a single nucleotide deletion results in a frame shift, reduced mRNA
levels, and absence of the protein.[14] The phenotype found in humans with the
deletion is termed Dubin-Johnson syndrome, an autosomal recessive disorder
characterized by chronic hyperbilirubinemia.[15] Reports also suggest that SN-38
may be a substrate for the mitoxantrone (Novantrone)-resistance half-transporter
(MXR) protein.[16,17] The effect of MXR on hepatic disposition of SN-38 has yet
to be determined.

Pretreatment of rats with phenobarbital, an inducer of UGT-1A1 and CYP 3A4,
was shown to enhance formation of SN-38G and diminish the area under the
concentration-time curve (AUC) for both SN-38 and irinotecan.[18] However,
valproic acid increased the AUC of SN-38. Additionally, phenobarbital combined
with irinotecan successfully treated a patient with Gilbert’s syndrome.[19]
Recent studies have demonstrated that patients receiving enzyme-inducing
antiepileptic drugs (EIAEDs) obtain lower plasma concentrations of
chemotherapeutic agents when administered at conventional doses.[20,21] Failure
to achieve adequate plasma drug levels may account in part for lack of
chemotherapy efficacy demonstrated in previous brain tumor trials.

The trial reported herein (NABTC-9801) is being conducted to determine the
dose-limiting toxicities, maximum tolerated dose, and antitumor activity of
irinotecan administered every 3 weeks to patients with progressive or recurrent
malignant glioma receiving EIAEDs (phase I portion). In the phase II portion of
the study, the antitumor activity of irinotecan including response rate, time to
tumor progression, and 6-month progression-free survival (primary end point)
will be determined. The influence of anticonvulsants on the metabolism and
elimination of irinotecan and its metabolites is also to be characterized, and
this is the main focus of this report.

Patients and Methods

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