Differences in clearance and sensitivity to Triazolam in American blacks as compared with whites

BACKGROUND: Inter-ethnic differences exist in both pharmocodynamics and pharmocokinetics. CYP3A is the most abundant cytochrome P450 enzyme in human liver and is responsible for the metabolism of a large number of drugs and xenobiotics. AIM OF STUDY: The purpose of the present study was to determine whether there are differences in the metabolism and drug responsiveness to triazolam, a substrate of CYP3A, in American blacks and whites. METHODS: Eight American blacks and eight age - and body weight- matched whites receved orally a triazolam 0.375 mg tablet in a double-blind placebo-controlled randomized study. Plasma concentrations and effects of triazolam were measured at multiple time points over 24 hours. The pharmacodynamics of triazolam were examined by measurement of postural sway, digital symbol substitution testing (DSST), and a visual analog scale (VAS) of drowiness. Sensitivity, or the drug effect at a given concentration, was determined. RESULTS: Following oral administration of triazolam, the AUC was significantly lower in blacks (625 +- 160 ng/ml/min) (P<0.05). The systemic clearance of triazolam was three and a half fold higher in blacks (6.6 +- 2.0 vs 1.8 +- 0.2 ml/min/kg in whites, P<0.05) resulting in a shorter elimination t 1/2 (98 +- 24 vs 199 +- 29 min, P<0.05). Triazolam significantly increased postural sway and drowsiness and impaired DSST in both groups. However, there was no significant differences between the two groups in drug effects such that a similar effect of triazolam was observed in blacks with lower plasma concentration. When compared to whites, the sensitivity to triazolam was significantly higher in blacks (P<0.05). CONCLUSIONS: This study demonstrates increased clearance and increased sensitivity to triazlam in American blacks. These findings may have major therapeutic implications in a racially diverse population. (AU)

The suppression by lipopolysaccharide of cytochrome P450-dependent renal vasodilation in the rat is mediated by nitric oxide

The isolated perfused kidney of the rat was used to examine the hypothesis that lipopolysaccharide-induced nitric oxide (NO) production inhibits cytochrome P450-dependent vasodilation. The vasodilator responses to arachidonic acid and bradykinin were examined as the response to arachidonic acid is wholly dependent, and that to bradykinin partly dependent on cytochrome P450 metabolism. In endotoxin-treated rats, the vasodilator response to arachidonic acid was inhibited, and those to bradykinin and acetylcholine were enhanced. Following treatment with phenobarbitone, the inducer of certain isoforms of cytochrome P450 enzymes, the vasodilator effects of all three agonists,especially that of arachidonic acid were amplified. Lipopolysaccharide inhibited the effect of phenobarbitone on the vasodilator effect of arachidonic acid and bradykinin but enhanced that of acetylcholine. The effect of lipopolysaccharide was antagonized by haemoglobin, a NO antagonist, and N (omega)- nitro-L-arginine, an inhibitor of NO synthase, suggesting that the inhibitory effect of lipopolysaccharide on arachidonic acid- and bradykinin-induced vasodilation was mediated by NO/NO synthase. N(omega)-Nitro-L-arginine enhanced vasodilation induced by arachidonic acid while that induced by bradykinin or acetylcholine was reduced, implying that endogenous NO inhibits vasodilator cytochrome P450 metabolites in the rat kidney. Pretreatment with dexamethasone, an inhibitor of inducible NO synthase, resulted in inhibition of the lipopolysaccharide modulation of arachidoni acid-induced vasodilation, suggesting that the inducible NO synthase is the target of the inhibitory effect of lipopolysaccharide. The inhibitory effect of lipopolysaccharide was mimicked by nitroprusside, the L-arginine-independent NO donor, and by L-arginine, the biosynthetic precusor of NO ...