title: Role of CYP1A2 in caffeine pharmacokinetics and metabolism: studies using mice deficient in CYP1A2.
abstract: We investigated the involvement of CYP1A2 in the pharmacokinetics and metabolism of caffeine using mice lacking its expression (CYP1A2 -/-). The half-life of caffeine elimination from blood was seven times longer in the CYP1A2 -/- than wild-type mice. The clearance was concomitantly eight times slower. No parameter that could affect the pharmacokinetics differed between CYP1A2-/-and wild-type mice such as creatinine for kidney function; alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and bilirubin for liver function; or albumin for protein binding. Other P450s CYP2A, 2B, 2C, 2EI, and 3A were also unchanged in the knockout animals. Caffeine 3-demethylated metabolites thought previously to be characteristic of CYP1A2 (especially 1-methylxanthine and I-methylurate) were also found in the urines of the CYP1A2-/-animals, although at 40% of the level found in wild-type mice. These data indicate that the clearance of caffeine in wild-type mice is primarily determined by CYP1A2.
authors.affiliation: National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Buters
authors.forename: B K
authors.initials: BK
authors.lastname: Tang
authors.forename: T
authors.initials: T
authors.lastname: Pineau
authors.forename: H V
authors.initials: HV
authors.lastname: Gelboin
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.forename: F J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002110:Caffeine / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D002110:Caffeine; D019388:Cytochrome P-450 CYP1A2