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

Anna M. Lee, Sharon Miksys, Rachel F. Tyndale

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)786-794
Number of pages9
JournalBritish Journal of Pharmacology
Volume148
Issue number6
DOIs
StatePublished - Jul 22 2006

Fingerprint

Phenobarbital
Nicotine
Haplorhini
Liver
Brain
Proteins
Bupropion
Cercopithecus aethiops
Pharmaceutical Preparations
Cytochrome P-450 CYP2B6
Saccharin
Phencyclidine
Nitrosamines
Pyramidal Cells
Putamen
Frontal Lobe
Smoking Cessation
Smoke
Cyclophosphamide
Cerebellum

Keywords

  • Brain protein induction
  • CYP2B6
  • In vivo kinetics
  • Monkey
  • Nicotine
  • Phenobarbital

Cite this

Phenobarbital increases monkey in vivo nicotine disposition and induces liver and brain CYP2B6 protein. / Lee, Anna M.; Miksys, Sharon; Tyndale, Rachel F.

In: British Journal of Pharmacology, Vol. 148, No. 6, 22.07.2006, p. 786-794.

Research output: Contribution to journalArticle

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abstract = "1. CYP2B6 is a drug-metabolizing enzyme expressed in the liver and brain that can metabolize bupropion (Zyban{\circledR}, 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.",
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N2 - 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.

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