Absorption and disposition of fluvastatin, an inhibitor of HMG-CoA reductase, in the rabbit.
The absorption and disposition of fluvastatin have been studied in the female rabbit. In naive rabbits receiving a single oral dose (1 mg kg-1) of [3H] fluvastatin, absorption was rapid and amounted to c. 90 per cent compared with an intravenous reference dose. The drug was subject to considerable first-pass effect, its absolute bioavailability being 46 per cent. The steady-state volume of distribution of fluvastatin was 0.29 +/- 0.04 l kg-1 while the total body clearance was 0.33 +/- 0.05 1 h-1 kg-1. The administered radioactivity was excreted predominantly in feces, with the renal pathway accounting for 28 +/- 4 per cent of the oral dose and 32 +/- 3 per cent of the intravenous dose. In pregnant rabbits on a multiple oral dosing regimen, 1 mg kg-1 day-1 beginning day 6 post-conception (p.c.), steady-state concentrations in maternal blood and tissues were achieved within 5 days. The concentrations in the reproductive organs were c. 25-50 per cent of that in maternal blood while those in the kidneys and liver were considerably higher. In contrast, radioactivity levels in the fetuses and amniotic fluid decreased significantly during repeated drug administration. The fetus: placenta and amniotic fluid: placenta concentration ratios declined from 0.92 and 0.97, respectively, on day 10 p.c. to 0.10 and 0.04, respectively, on day 18 p.c., indicating a limited transfer of fluvastatin and/or its metabolite(s) across the placenta at the later stage of pregnancy. After cessation of dosing, radioactivity levels in all tissues and fluids showed a progressive and nearly parallel decline, suggesting no tissue retention of the drug.
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Department of Drug Metabolism, Sandoz Research Institute, East Hanover, New Jersey 07936.
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D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008431:Maternal-Fetal Exchange; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011817:Rabbits; D014018:Tissue Distribution
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin