Increased hepatic nicotine elimination after phenobarbital induction in the conscious rat

Journal Article · Sat Sep 15 04:00:00 EDT 1990 · Toxicology and Applied Pharmacology; (USA)

DOI:https://doi.org/10.1016/0041-008X(90)90142-H· OSTI ID:6170824

Foth, H; Walther, U I; Kahl, G F ^[1]

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1. Univ. of Goettingen (Germany, F.R.)

Elimination parameters of (14C)nicotine in conscious rats receiving nicotine (0.3 mg/kg) either intravenously or orally were studied. The oral availability of unchanged nicotine, derived by comparison of the respective areas under the concentration vs time curves (AUC), was 89%, indicating low hepatic extraction ratios of about 10%. Pretreatment of rats with phenobarbital (PB) markedly increased hepatic first-pass extraction of nicotine. The oral availability of unchanged nicotine in plasma dropped to 1.4% of the corresponding values obtained from PB-treated rats receiving nicotine iv. After PB pretreatment, the clearance of iv nicotine was increased approximately twofold over controls, much less than the observed more than ninefold increase of hepatic first-pass extraction. It is assumed that extrahepatic metabolism contributed significantly to the rapid removal of nicotine from the plasma. The elimination of cotinine, originating from nicotine administered either po or iv, was significantly increased by PB pretreatment, as determined by the ratio of corresponding AUCs. The pattern of nicotine metabolites in urine also indicated an increase in the rate of cotinine metabolic turnover. The amount of norcotinine in the organic extract of urine paralleled PB microsomal enzyme induction. The ratio between urinary concentrations of the normetabolite and cotinine correlated strongly with the PB-induced state of rat liver. This may be a suitable indicator of PB-inducible hepatic cytochrome P450 isoenzyme(s). Since smoking habits in man are feedback-regulated by nicotine plasma concentrations, a similar increase of nicotine elimination by microsomal enzyme induction in man may be of relevance for tobacco consumption.

• OSTI ID: 6170824
• Journal Information: Toxicology and Applied Pharmacology; (USA), Journal Name: Toxicology and Applied Pharmacology; (USA) Vol. 105:3; ISSN TXAPA; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

550501* -- Metabolism-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ALKALOIDS
AMINES
ANESTHETICS
ANIMALS
ANTICONVULSANTS
AUTONOMIC NERVOUS SYSTEM AGENTS
AZINES
AZOLES
BARBITURATES
BIOLOGICAL EFFECTS
CARBON 14 COMPOUNDS
CENTRAL NERVOUS SYSTEM DEPRESSANTS
DRUGS
HETEROCYCLIC COMPOUNDS
HYPNOTICS AND SEDATIVES
INJECTION
INTAKE
INTRAVENOUS INJECTION
ISOENZYMES
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
MAMMALS
METABOLISM
NICOTINE
ORAL ADMINISTRATION
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
PARASYMPATHOLYTICS
PARASYMPATHOMIMETICS
PHENOBARBITAL
PYRIDINES
PYRIMIDINES
PYRROLES
PYRROLIDINES
RATS
RODENTS
TRACER TECHNIQUES
VERTEBRATES