ROLE OF CYP1A2 IN CAFFEINE PHARMACOKINETICS AND METABOLISM - STUDIES USING MICE DEFICIENT IN CYP1A2

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 long er in the CYP1A2 -/- than wild-type mice, The clearance was concomitan tly eight times slower. No parameter that could affect the pharmacokin etics differed between CPP1A2 -/- and wild-type mice such as creatinin e for kidney function; alanine aminotransferase, aspartate aminotransf erase, alkaline phosphatase and bilirubin for liver function; or album in for protein binding. Other P450s CYP2A, 2B, 2C, 2E1, and 3A were al so unchanged in the knockout animals. Caffeine 3-demethylated metaboli tes thought previously to be characteristic of CYP1A2 (especially l-me thylxanthine and 1-methylurate) were also found in the urines of the C YP1A2 -/- animals, although at 40% of the level found in wild-type mic e. These data indicate that the clearance of caffeine in wild-type mic e is primarily det ermined by CYP1A2.