Abstract
This study was to investigate the effect of lovastatin on the bioavailability or pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of lovastatin (0.3 or 1.0 mg/kg). The pharmacokinetic parameters of verapamil were significantly altered by the presence of lovastatin compared to the control group (given verapamil alone). The presence of lovastatin significantly (p < 0.05, 0.3 mg/kg; p < 0.01, 1.0 mg/kg) increased the total area under the plasma concentration-time curve (AUC) of verapamil by 26.5–64.8%, and the peak plasma concentration (Cmax) of verapamil by 34.1–65.9%. Consequently, the relative bioavailability (R.B.) of verapamil was increased by 1.27- to 1.65-fold than that of the control group. However, there was not significant change in the time to reach the peak plasma concentration (Tmax) and the terminal half-life (t1/2) of verapamil in the presence of lovastatin. The AUC and Cmax of norverapamil were significantly (p < 0.05) higher than those of presence of 1.0 mg/kg of lovastatin compared with the control group. However, there was no significant change in the metabolite-parent ratio (M.R.) of norverapamil in the presence of lovastatin. The presence of lovastatin significantly enhanced the oral bioavailability of verapamil. The enhanced oral bioavailability of verapamil may be due to inhibition both of the CYP3A-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or in liver by the presence of lovastatin.
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References
Azie, N. E., Brater, D. C., Becker, P. A., Jones, D. R., and Hall, S. D., The interaction of diltiazem with lovastatin and pravastatin. Clin. Pharmacol. Ther., 64, 369–377 (1998).
Benet, L. Z., Cummins, C. L., and Wu, C. Y., Transporterenzyme interactions: implications for predicting drugdrug interactions from in vitro data. Curr. Drug. Metab., 4, 393–398 (2003).
Choi, D. H., Shin, W. G., and Choi, J. S., Drug interaction between oral atorvastatin and verapamil in healthy subjects: effects of atorvastatin on the pharmacokinetics of verapamil and norverapamil. Eur. J. Clin. Pharmacol., 64, 445–449 (2008).
Choi, D. H., Chang, K. S., Hong, S. P., Choi, J. S., and Han, H. K., Effect of atorvastatin on the intravenous and oral pharmacokinetics of verapamil in rats. Biopharm. Drug Dispos., 29, 45–50 (2008).
Cummins, C. L., Jacobsen, W., and Benet, L. Z., Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J. Pharmacol. Exp. Ther., 300, 1036–1045 (2002).
Döppenschmitt, S., Spahn-Langguth, H., Regårdh, C. G., and Langguth, P., Role of P-glycoprotein mediated secretion in absorptive drug permeability: an approach using passive membrane permeability and affinity to P-glycoprotein. J. Pharm. Sci., 88, 1067–1072 (1999).
Eichelbaum, M., Ende, M., Remberg, G., Schomerus, M., and Dengler, H. J., The metabolism of DL-[14C]verapamil in man. Drug Metab. Dispos., 7, 145–148 (1979).
Eichelbaum, M., Mikus, G., and Vogelgesang, B., Pharmacokinetics of (+)-, (−)- and (±)-verapamil after intravenous administration. Br. J. Clin. Pharmacol., 17, 453–458 (1984).
Fleckenstein, A., Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle. Annu. Rev. Pharmacol. Toxicol., 17, 149–166 (1977).
Gould, B. A., Mann, S., Kieso, H., and Subramanian, V. B., Raftery EB. The 24-hour ambulatory blood pressure profile with verapamil. Circulation, 65, 22–27 (1982).
Halpin, R. A., Ulm, E. H., Till, A. E., Kari, P. H., Vyas, K. P., Hunninghake, D. B., et al., Biotransformation of lovastatin. V. Species differences in in vivo metabolite profiles of mouse, rat, dog, and human. Drug Metab. Dispos., 21, 1003–1011 (1993).
Johnson, B. M., Chen, W., Borchardt, R. T., Charman, W. N., and Porter, C. J., A kinetic evaluation of the absorption, efflux, and metabolism of verapamil in the autoperfused rat jejunum. J. Pharmacol. Exp. Ther., 305, 151–158 (2003).
Khandwala, H. M., Lipid lowering inefficacy of high-dose statin therapy due to concurrent use of phenytoin. South. Med. J., 99, 1385–1387 (2006).
Kubota, T., Fujisaki, K., Itoh, Y., Yano, T., Sendo, T., and Oishi, R., Apoptotic injury in cultured human hepatocytes induced by HMG-CoA reductase inhibitors. Biochem. Pharmacol., 67, 2175–2186 (2004).
Lewis, G. R., Morley, K. D., Lewis, B. M., and Bones, P. J., The treatment of hypertension with verapamil. NZ. Medical. J., 87, 351–354 (1978).
Mason, R. P., A rationale for combined therapy with a calcium channel blocker and a statin: evaluation of basic and clinical evidence. Curr. Drug Targets Cardiovasc. Haematol. Disord., 5, 489–501 (2005).
Mousa, O., Brater, D. C., Sunblad, K. J., and Hall, S. D., The interaction of diltiazem with simvastatin. Clin. Pharmacol. Ther., 67, 267–274 (2000).
Neuvonen, P. J. and Jalava, K. M., Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. Clin. Pharmacol. Ther., 60, 54–61 (1996).
Saitoh, H. and Aungst, B. J., Possible involvement of multiple P-glycoprotein-mediated efflux systems in the transport of verapamil and other organic cations across rat intestine. Pharm. Res., 12, 1304–1310 (1995).
Schomerus, M., Spiegelhalder, B., Stieren, B., and Eichelbaum, M., Physiological disposition of verapamil in man. Cardiovasc. Res., 10, 605–612 (1976).
Tobert, J. A., Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat. Rev. Drug Discov., 2, 517–526 (2003).
Wang, E., Casciano, C. N., Clement, R. P., and Johnson, W. W., HMG-CoA reductase Inhibitors (statins) characterized as direct inhibitors of P-glycoprotein. Pharm. Res., 18, 800–806 (2001).
Wolozin, B., Kellman, W., Ruosseau, P., Celesia, G. G., and Siegel, G., Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch. Neurol., 57, 1439–1443 (2000).
Zhang, Y., Guo, X., Lin, E. T., and Benet, L. Z., Overlapping substrate specificities of cytochrome P450 3A and Pglycoprotein for a novel cysteine protease inhibitor. Drug Metab. Dispos., 26, 360–366 (1998).
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Hong, SP., Chang, KS., Koh, YY. et al. Effects of lovastatin on the pharmacokinetics of verapamil and its active metabolite, norverapamil in rats: Possible role of P-glycoprotein inhibition by lovastatin. Arch. Pharm. Res. 32, 1447–1452 (2009). https://doi.org/10.1007/s12272-009-2015-2
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DOI: https://doi.org/10.1007/s12272-009-2015-2