title: Pharmacokinetic interaction between isradipine and lovastatin in normal, female and male volunteers.
abstract: 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.
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, USA.
authors.forename: L X
authors.initials: LX
authors.lastname: Zhou
authors.forename: D K
authors.initials: DK
authors.lastname: Finley
authors.forename: A E
authors.initials: AE
authors.lastname: Hassell
authors.forename: J L
authors.initials: JL
authors.lastname: Holtzman
mesh_terms: D000328:Adult; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004347:Drug Interactions; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017275:Isradipine / Q000493:pharmacokinetics*; D008148:Lovastatin / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D012737:Sex Factors
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D008148:Lovastatin; D017275:Isradipine