Cytochrome P450-inducing antiepileptics increase the clearance of vincristine in patients with brain tumors.
BACKGROUND
Vincristine is at least partly metabolized by CYP3A4. We have studied the possible effect of the CYP3A4-inducing antiepileptic agents carbamazepine and phenytoin on the pharmacokinetics of vincristine.


METHODS
Fifteen adult patients with brain tumors receiving combination chemotherapy with procarbazine, lomustine, and vincristine volunteered for this open parallel-group study. Nine of the patients used either carbamazepine or phenytoin and six of the patients used no obvious CYP3A4-inducing medication. After intravenous infusion of 2 mg vincristine, timed blood samples were collected up to 24 hours. Plasma vincristine concentrations were measured by liquid chromatography-tandem mass spectrometry. The pharmacokinetics of vincristine were compared between the two patient groups.


RESULTS
The systemic clearance of vincristine was 63% higher (925 +/- 61 versus 569 +/- 76 mL/min [mean +/- SEM]; P = .004), the elimination half-life was 35% shorter (12.7 +/- 0.6 versus 19.4 +/- 3.6 hours; P = .13), and the total area under the plasma concentration-time curve was 43% smaller (37.3 +/- 2.4 versus 65.1 +/- 10.1 ng x h/mL; P = .04) in patients who were receiving carbamazepine or phenytoin than in the control group.


CONCLUSIONS
Drugs that induce CYP3A4 can increase the elimination of vincristine. Further studies are needed to determine whether the increased clearance of vincristine by carbamazepine or phenytoin decreases the efficacy of vincristine.
Villikka
K
K
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
Kivistö
K T
KT
Mäenpää
H
H
Joensuu
H
H
Neuvonen
P J
PJ
D000328:Adult; D000927:Anticonvulsants / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000097:blood* / Q000188:drug therapy; D002220:Carbamazepine / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008130:Lomustine / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D010672:Phenytoin / Q000494:pharmacology*; D011344:Procarbazine / Q000493:pharmacokinetics; D014750:Vincristine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D000927:Anticonvulsants; D002220:Carbamazepine; D011344:Procarbazine; D014750:Vincristine; D010672:Phenytoin; D008130:Lomustine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human