Hepatic drug metabolism after phenobarbital and diphenylhydantoin administration in the rat—influence of vitamin D 3 status

Abstract

Measurements of aniline hydroxylation, aminopyrine N-demethylation and cytochrome P-450 content after a 3-week treatment with phenobarbital (PB), diphenylhydantoin (DPH) or a combination of the two drugs were undertaken during normal vitamin D status (D +) and vitamin D deficiency (D −) with or without vitamin D 3(D 3) supplementation. Serum calcium concentrations were reduced after D deprivation but responded by a significant increase toward normal values to a single pharmacological dose of D 3. Serum phosphorus concentrations were also slightly raised by the supplementation. Even in the presence of higher cytochrome P-450 content in D − rats, aniline hydroxylase and aminopyrine N-demethylase activities were lower in D − than in D + animals. These two enzymatic parameters, as well as cytochrome P-450 content, were increased by anticonvulsant (ACV) drug treatment regardless of the D nutritional status. The in vivo hexobarbital sleeping time was shortened by ACV drugs but the sleeping time tended to be longer in D − than in D + rats. Supplementation with 1000 I.U. of D 3, lowered aniline hydroxylase activity both in D + and D− animals; the supplementation had no effect on aminopyrine N-demethylase activity in D + animals but had an inhibitory effect after PB and a stimulatory effect after DPH treatment in D− animals. Cholecalciferol supplementation lowered cytochrome P-450 content toward normal values in D− rats while it had no effect in D + animals. These observations suggest that (1) PB and DPH pretreatment do not alter the normal response of serum calcium and phosphorus to a single pharmacological dose of D 3; (2) in a state of vitamin D deficiency accompanied by hypocalcemia, the inducing capacity of PB and DPH on the liver mixed function oxidase system is not lost; (3) under certain circumstances, vitamin D 3, can influence the catalytic activity of the mono-oxygenase complex; (4) cytochrome P-450 is influenced by vitamin D deficiency and/or changes in extracellular calcium but the forms induced by PB and DPH may not necessarily be the ones specifically involved in vitamin D metabolism.