Genetic Differences in Phenytoin Pharmacokinetics In vivo Clearance andin vitro Metabolism among Inbred Strains of Mice

Abstract

Plasma phenytoin elimination rates were examined among twelve inbred strains of mice. Two populations are identified--the 'fast metabolizers' (BALB/cN, C57BL/6N, C57BL/6J, AKR/N, AKR/J and C3H/HeN) having almost exactly twice as rapid an elimination rate as the 'slow metabolizers' (CL/FR, CBA/J, DBA/2N, STAR/N, SJL/N, DBA/2J and RF/N). The difference in elimination rate between C57BL/6J and DBA/2J cannot be accounted for by dissimilarities in volume of distribution. The phenytoin elimination rate in the (C57BL/6J)(DBA/2J)F1 heterozygote is expressed as an additive trait. A good correlation exists between phenytoin elimination rates in vivo and phenytoin metabolism by liver microsomes in vitro, as determined by a newly described assay using high-performance liquid chromatography. 3-Methylcholanthrene pretreatment does not enhance phenytoin elimination or metabolism. The cytochrome P-450-mediated monoxygenase metabolism of phenytoin is not associated with the Ah locus or with coat color among progeny of the (C57BL/6N)(DBA/2N) F1 x DBA/2N backcross. Phenobarbital pretreatment enhances phenytoin elimination and metabolism in both a fast metabolizer (C57BL/6N) and a slow metabolizer (DBA/2N) strain. Phenobarbital pretreatment probably also induces non-P-450 enzymes, such as those which form the phenytoin dihydrodiol and the glucuronide and glutathione conjugates, in addition to inducing one or more forms of P-450 that oxygenate phenytoin. These data probably reflect allelic differences in a structural gene encoding for one (or more) form(s) of control cytochrome P-450 that metabolizes phenytoin, rather than allelic differences in a regulatory gene. The marked sensitivity of inbred mouse strains CL/FR and A/J and the marked resistance of STAR/N, Swiss-Webster, and C57BL/6 to phenytoin-induced cleft lip and/or palate cannot be explained by genetic differences in phenytoin elimination rates or liver microsomal metabolism in vitro, as measured by the methods described in this report.