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Objective: To screen the inhibitory effects of H1-antihistamines on hepatic bufuralol 1'-hydroxylation and on tolbutamide 4-methylhydroxylation in human liver microsomes., Methods: Bufuralol 1'-hydroxylation and tolbutamide 4-methylhydroxylation were used as index reactions for CYP2D6 and CYP2C9, respectively. The metabolites of both reactions were measured using high-performance liquid chromatography and were used as indicators of whether CYP2D6 or CYP2C9 activities were inhibited or unaffected by the agents., Results: All five H1-antihistamines studied showed a concentration-dependent inhibition of CYP2D6-mediated bufuralol 1'-hydroxylation with 50% inhibitory concentration (IC50) values of 32-109 microM. Cyclizine and promethazine showed inhibitory effects on tolbutamide 4-methylhydroxylation with IC20 values of 85 microM and 88 microM, respectively. Tripelennamine, chlorpheniramine, and diphenhydramine showed no inhibitory effects on CYP2C9., Conclusion: All five H1-antihistamines studied inhibited CYP2D6 markedly, but only cyclizine and promethazine inhibited CYP2C9 at concentrations above that usually seen in plasma. Promethazine and chlorpheniramine inhibited CYP2D6 at concentrations that are very close to their therapeutic plasma concentrations. Further studies in humans, especially in poor metabolizers of CYP2D6, will be required to confirm these findings.

In the present study the effect of metastatic liver disease on hepatic drug metabolism has been examined by studying the pharmacokinetics of antipyrine and the urinary excretion of antipyrine and its three major metabolites (4-hydroxyantipyrine, norantipyrine, and 3-hydroxymethylantipyrine) in 12 patients with extensive metastatic liver disease, and in 12 matched healthy controls. In the patients total liver volume, the volume of the liver parenchyma, and the volume of the liver metastases were determined by computed tomography. The volume of liver metastases always exceeded 35% of the total liver volume. There were no significant differences between the patients and controls in plasma half-life, plasma clearance, or apparent volume of distribution of antipyrine. The cumulative urinary excretion of antipyrine and its three major metabolites was significantly lower in patients [44 (18) %] than in controls [71 (8) %]. The excretion of antipyrine itself was unchanged and the decrease in cumulative excretion was due to reduced excretion of the three metabolites. The results show that the activity of the hepatic mixed function oxidases was not impaired even in patients with extensive metastatic liver disease. This may be because liver metastases do not cause a corresponding reduction in the volume of normal hepatic parenchyma. The decreased urinary excretion of the three major metabolites of antipyrine, which are mainly glucuronidated, may have been due to an alteration in the process of conjugation.

The influence of 2 weeks oral intake of nifedipine (2 x 20 mg) on the oxidative metabolism of antipyrine was investigated in 12 normal volunteers, who had 1050 mg antipyrine solution orally before and after the course of nifedipine. There were no statistically significant differences in the saliva pharmacokinetic parameters of antipyrine on both occassions. However, the metabolite profile of antipyrine in urine showed a significant reduction in the amount of norantipyrine excreted after compared to that before nifedipine administration (16.5 vs 19.6%). This may have implications for drugs that share a similar demethylation pathway with norantipyrine.