Phenobarbital increases monkey in vivo nicotine disposition and induces liver and brain CYP2B6 protein.
1. CYP2B6 is a drug-metabolizing enzyme expressed in the liver and brain that can metabolize bupropion (Zyban), a smoking cessation drug), activate tobacco-smoke nitrosamines, and inactivate nicotine. Hepatic CYP2B6 is induced by phenobarbital and induction may affect in vivo nicotine disposition, while brain CYP2B6 induction may affect local levels of centrally acting substrates. We investigated the effect of chronic phenobarbital treatment on induction of in vivo nicotine disposition and CYP2B6 expression in the liver and brain of African Green (Vervet) monkeys. 2. Monkeys were split into two groups (n=6 each) and given oral saccharin daily for 22 days; one group was supplemented with 20 mg kg(-1) phenobarbital. Monkeys were given a 0.1 mg kg(-1) nicotine dose subcutaneously before and after treatment. 3. Phenobarbital treatment resulted in a significant, 56%, decrease (P=0.04) in the maximum nicotine plasma concentration and a 46% decrease (P=0.003) in the area under the concentration-time curve. Phenobarbital also increased hepatic CYP2B6 protein expression. In monkey brain, significant induction (P<0.05) of CYP2B6 protein levels was observed in all regions tested (caudate, putamen, hippocampus, cerebellum, brain stem and frontal cortex) ranging from 2-fold to 150-fold. CYP2B6 expression was induced in specific cells, such as frontal cortical pyramidal cells and thalamic neurons. 4. In conclusion, chronic phenobarbital treatment in monkeys resulted in increased in vivo nicotine disposition, and induced hepatic and brain CYP2B6 protein levels and cellular expression. This induction may alter the metabolism of CYP2B6 substrates including peripherally acting drugs such as cyclophosphamide and centrally acting drugs such as bupropion, ecstasy and phencyclidine.
Lee
Anna M
AM
Centre for Addiction and Mental Health, Department of Pharmacology, University of Toronto, Medical Sciences Building, Room 4336, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Miksys
Sharon
S
Tyndale
Rachel F
RF
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000032:analysis / Q000096:biosynthesis*; D001921:Brain / Q000201:enzymology*; D002522:Chlorocebus aethiops; D065702:Cytochrome P-450 CYP2B6; D004790:Enzyme Induction / Q000187:drug effects; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology*; D008297:Male; D009538:Nicotine / Q000493:pharmacokinetics*; D010089:Oxidoreductases, N-Demethylating / Q000032:analysis / Q000096:biosynthesis*; D010634:Phenobarbital / Q000494:pharmacology*
D009538:Nicotine; D001189:Aryl Hydrocarbon Hydroxylases; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D010634:Phenobarbital