Pharmacokinetic interaction between isradipine and lovastatin in normal, female and male volunteers.

We have examined the pharmacokinetic interaction between isradipine and lovastatin in six male and six female, healthy, normotensive, human subjects after a single dose and after treatment for 5 days. The isradipine plasma concentrations were determined by a radioimmunoassay and the lovastatin serum concentrations by gas chromatography-mass spectrometry (GC/MS) and by the inhibition of the 3-hydroxy-3-methylglutaric-coenzyme reductase activity. We found that the apparent serum concentrations of lovastatin were 4- to 6-fold higher in the reductase-inhibition assay than the GC/MS assay, suggesting that the bulk of the reductase inhibition is due to active metabolites. The peak and the time-to-peak concentrations were unaffected by the treatments, either after the first dose or after continued administration. In male subjects, after repeated doses of isradipine, the lovastatin area under the time-concentration curves (AUCs) decreased by 40% as determined by the GC/MS assay (P < .001) and 20% as determined by the reductase-inhibition assay (P < .0022). In the female subjects, isradipine treatment decreased the lovastatin AUCs as determined by the GC/MS assay, but this was not statistically significant due to a high variance. Furthermore, in the female subjects, isradipine had no effect on the lovastatin AUCs as determined by the reductase-inhibition assay. Because the lovastatin peak and the time-to-peak concentrations were unaffected by isradipine treatment, the decreased lovastatin AUCs were probably not due to altered intestinal absorption. More likely, because lovastatin has a high hepatic clearance, the decreased AUCs seen after isradipine treatment could be due to increases in the clearance of lovastatin secondary to increased hepatic blood flow.

The effects of several weeks of ethanol consumption on ethanol kinetics in normal men and women.

We examined in normal men and women the effects of chronic ethanol consumption and the coadministration of cimetidine and ranitidine on the kinetics of ethanol. We found that the consumption of 45 gm ethanol per day for 3 weeks increased the apparent volume of distribution of ethanol in men from 732 to 884 ml/kg (P less than 0.01) but had no such effect in women (697 ml/kg before ethanol and 746 ml/kg after chronic ethanol consumption). This combined therapy had no effect on the rate of ethanol disappearance in either sex. In men the rate of disappearance was 165 mg/L/hr before and 168 mg/L/hr after chronic consumption, while in women the respective values were 209 and 203 mg/L/hr. The addition of either cimetidine or ranitidine had no effect on either parameter compared with values observed on day 22 of the study. In view of the known inhibitory effects of cimetidine on cytochrome P-450-dependent enzymes, our data suggest that this enzyme system does not metabolize a significant fraction of ingested ethanol in subjects who have consumed moderate doses of alcohol for several weeks.