Phenobarbital increases monkey in vivo nicotine disposition and induces liver and brain CYP2B6 protein

Abstract

1 CYP2B6 is a drug-metabolizing enzyme expressed in the liver and brain that can metabolize bupropion (Zyban s , 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 ¼ 6 each) and given oral saccharin daily for 22 days; one group was supplemented with 20 mg kg À1 phenobarbital. Monkeys were given a 0.1 mg kg À1 nicotine dose subcutaneously before and after treatment. 3 Phenobarbital treatment resulted in a significant, 56%, decrease (P ¼ 0.04) in the maximum nicotine plasma concentration and a 46% decrease (P ¼ 0.003) in the area under the concentration-time curve. Phenobarbital also increased hepatic CYP2B6 protein expression. In monkey brain, significant induction (Po0.05) 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.

Expression, microsomal and mitochondrial activities of cytochrome P450 enzymes in brain regions from control and phenobarbital-treated rabbits

“…Although a limited induction of CYP 2B by phenobarbital and other agents has been reported in brain of some other species (Dhawan et al, 1999;Bhagwat et al, 1995;Miksys et al, 2000;Rosenbrock et al, 1999;Lee et al, 2006), the present study shows that in rabbit phenobarbital (80 mg/kg for four days) failed to induce brain CYP 2B 4/5 activity. Accordingly, there was no apparent change in the expression of CYP 2B4/5 in the brain regions when it was quantitatively assayed by real time PCR.…”

Identification and Characterization of CYP2B6 cDNA in Cynomolgus Macaques (Macaca fascicularis)

“…Cynomolgus CYP2B-like protein cross-reactive with rat CYP2B1 antibodies has been induced in the liver by phenobarbital treatment [2]. Similarly, CYP2B protein has also been induced in the liver and brain of African green monkeys by treatment with phenobarbital or nicotine, with the latter being to a lesser extent [7,13]. These results indicate that phenobarbital also induces expression of CYP2B proteins in primates in vivo.…”

Differential Effects of Nicotine Treatment and Ethanol Self-Administration on CYP2A6, CYP2B6 and Nicotine Pharmacokinetics in African Green Monkeys

“…for in vitro nicotine metabolism in AGM hepatic microsomes is 29.1 Ϯ 8.6 M (n ϭ 6) (Schoedel et al, 2003), which is comparable with the apparent k m value of 64 Ϯ 32.7 M (n ϭ 31) in human hepatic microsomes (Messina et al, 1997). Consistent with these similarities, the plasma half-life for nicotine ranges from 1 to 4 h in both AGMs and humans (Hukkanen et al, 2005;Lee et al, 2006). AGMs are also an important model for complex human behaviors and are routinely used in alcohol research because they will voluntarily self-administer alcohol at levels comparable with human consumption (Ervin et al, 1990).…”