Objective: To identify the differences in esterase hydrolysis of lovastatin between male and female volunteers.
Study design and participants: Data for plasma concentration and area under the concentration-time curve until the last measured concentration (AUCt) of lovastatin and its active metabolite lovastatin-β-hydroxy acid (mevinolinic acid) were obtained from a randomised, crossover bioequivalence study in 36 subjects (18 females and 18 males).
Methods: Participants received a single 80mg oral dose of two different formulations of lovastatin (formulations I and II). Plasma lovastatin and lovastatin-β-hydroxy acid concentrations were determined according to validated methods involving gas chromatography-mass spectrometry.
Results: The group of female volunteers showed a higher yield of the active metabolite lovastatin-β-hydroxy acid than the group of males (p < 0.002). This difference was not related to the bodyweight of the two groups. In both male and female groups, a subject-dependent yield of lovastatin-β-hydroxy acid was demonstrated, which was independent of the formulation. The variation in plasma/liver hydrolysis resulted in a fan-shaped distribution of datapoints when the AUCt of lovastatin was plotted against that of the hydroxy acid metabolite. In the fan of datapoints, subgroups could be distinguished, each showing a different regression line and with a different y-intercept (AUCt of lovastatin-β-hydroxy acid). It was possible to discriminate between hydrolysis of lovastatin by plasma/liver or tissue esterase activity. The three subgroups of subjects (males/females) showing a different but high yield of lovastatin-β-hydroxy acid can be explained by variable hydrolysis by plasma and hepatic microsomal and cytosolic carboxyesterase activity.
Conclusion: This study showed clearly that in addition to subject-dependent hydrolysis of lovastatin to the active metabolite, males tend to hydrolyse less than females. Therefore, the dosage of lovastatin should be individualised with reference to plasma concentration or clinical effect.
Simvastatin Lovastatin Esterase Activity Liver Esterase Primary Active Metabolite
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access.
Alberts AW, Chen J, Kuron G, et al. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci U S A 1980; 77: 3957–61PubMedCrossRefGoogle Scholar
Grundy SM, Vega GL. Influence of mevinolin on metabolism of low density lipoproteins in primary moderate hypercholesterolemia. J Lipid Res 1985; 26: 1464–75PubMedGoogle Scholar
Hoffman WF, Alberts AW, Anderson PS, et al. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 4. Side chain ester derivatives of mevinolin. J Med Chem 1986; 29: 849–52PubMedCrossRefGoogle Scholar
Lennernäs H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Clin Pharmacokinet 1997; 32: 403–25PubMedCrossRefGoogle Scholar
Sirtori CR. Tissue selectivity of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors. Pharmacol Ther 1993; 60: 431–59PubMedCrossRefGoogle Scholar
Barr WH. The role of intestinal metabolism on bioavailability. In: Welling PG, Tse FLS, Dighe SV, et al. Pharmaceutical bioequivalence. New York: Marcel Dekker, 1991: 149–68Google Scholar
DeWaziers I, Cugnenc PH, Yang CS, et al. Cytochrome P450 isoenzymes, epoxide hydrolase and glutathione transferase in rat and human hepatic and extrahepatic tissues. J Pharmacol Exp Ther 1990; 253: 387–94Google Scholar
Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet 1993; 24: 195–202PubMedCrossRefGoogle Scholar
Tang BK, Kalow W. Variable activation of lovastatin by hydrolytic enzymes in human plasma and liver. Eur J Clin Pharmacol 1995; 47: 449–51PubMedCrossRefGoogle Scholar
Cheng H, Rogers JD, Sweany AE, et al. Influence of age and gender on the plasma profiles of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitory activity following multiple doses of lovastatin and simvastatin. Pharm Res 1992; 9: 1629–34PubMedCrossRefGoogle Scholar
Duggan DE, Chen IW, Bayne WF, et al. The physiological disposition of lovastatin. Drug Metab Dispos 1989; 17: 166–73PubMedGoogle Scholar
Jacobsen W, Kirchner G, Hallensleben K, et al. Comparison of cytochrome P450 dependent metabolism and drug interactions of the 3HMG-CoA reductase inhibitors lovastatin and pravastatin in the liver. Drug Metab Dispos 1999; 27: 173–9PubMedGoogle Scholar
Halpin RA, Ulm EH, Till AE, et al. Biotransformation of lovastatin. Species differences in in vivo metabolite profiles in mouse, rat, dog and human. Drug Metab Dispos 1993; 21: 1003–11PubMedGoogle Scholar
Vickers S, Duncan CA, Chen IW, et al. Metabolic disposition studies on simvastatin, a cholesterol lowering prodrug. Drug Metab Dispos 1989; 18: 138–45Google Scholar
Vyas KP, Kari PH, Pitzenberger SM. Regioselectivity and stereoselectivity in the metabolism of HMG-CoA reductase inhibitors. Biochem Biophys Res Commun 1990; 166: 1155–62PubMedCrossRefGoogle Scholar
Wang RW, Karl PH, Lu AYH, et al. Biotransformation of lovastatin. Identification of cytochrome P4503A proteins as the major enzymes responsible for the oxidative metabolism of lovastatin in rat and human liver microsomes. Arch Biochem Biophys 1991; 290: 355–61PubMedCrossRefGoogle Scholar
Transon C, Leemann T, Dayer P. In vitro comparative inhibition profiles of major drug metabolising cytochrome P450 isoenzymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 1996; 50: 209–15PubMedCrossRefGoogle Scholar
Kivistö KT, Bookjans G, Fromm MF, et al. Expression of CYP3A4, CYP3A5 and CYP3A7 in human duodenal tissue. Br J Clin Pharmacol 1996; 42: 387–9PubMedCrossRefGoogle Scholar
Reynolds JEF. Lovastatin. In: Martindale. The Extra Pharmacopoeia, 30th ed. London: Pharmaceutical Press, 1993: 990–1Google Scholar
Lilja JJ, Kivistö KT, Neuvonen PJ. Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin. Clin Pharmacol Ther 2000; 68: 384–90PubMedCrossRefGoogle Scholar
Lilja JJ, Kivistö KT, Neuvonen PJ. Grapefruit juice-simvastatin interaction; effect on serum concentrations of simvastatin, simvastatin acid and HMG-CoA reductase inhibitors. Clin Pharmacol Ther 1998; 64: 477–83PubMedCrossRefGoogle Scholar
Vree TB, Dammers E, Ulc I, et al. Variable plasma/liver and tissue esterase hydrolysis of simvastatin in healthy volunteers after a single oral dose. Clin Drug Invest 2001; 21: 643–52CrossRefGoogle Scholar
Vree TB, Dammers E, Exler PS, et al. Liver and gut mucosa acetylation of mesalazine in healthy volunteers. Int J Clin Pharmacol Ther 2000; 38: 514–22PubMedGoogle Scholar
Neuvonen PJ, Kantola T, Kivistö KT. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther 1998; 63: 332–41PubMedCrossRefGoogle Scholar
Pan HY, Devault AR, Wand-Iverson D, et al. Comparative pharmacokinetics and pharmacodynamics of pravastatin and lovastatin. J Clin Pharmacol 1990; 30: 1128–35PubMedGoogle Scholar
Back DJ, Orme ML. Pharmacokinetic drug interactions with oral contraceptives. Clin Pharmacokinet 1990; 18: 472–84PubMedCrossRefGoogle Scholar
Christians U, Jacobsen W, Floren LC. Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in fransplant patients: are the statins mechanistically similar? Pharmacol Ther 1998; 80: 1–34PubMedCrossRefGoogle Scholar
Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs 1995; 50: 222–39PubMedCrossRefGoogle Scholar
Bottorff M. Fire and forget?. Pharmacological considerations in coronary care. Atherosclerosis 1999; 147Suppl 1: S23–30PubMedCrossRefGoogle Scholar
Burnstein AH, Reiss WG, Kantor E, et al. Cytochrome P450 3A4 activity in premenopausal and postmenopausal women, based on 6-beta-hydroxycortisol/cortisol ratios. Pharmacotherapy 1998; 18: 1271–6Google Scholar
Kyrklund C, Backman JT, Kivistö KT, et al. Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin Pharmacol Ther 2001; 69: 340–5PubMedCrossRefGoogle Scholar