Verapamil pharmacokinetic

Schwartz JB, Capili H, Daugherty J. Aging of women alters S-verapamil pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 1994 55 509-17. 

McTavish, D., Sorkin E. M., Verapamil an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension, Drugs 1989, 38, 19-76. 

Besides catalyzing styrene and benzaldehyde, CYP enzymes play an important role in the metabolism of endogenous compounds as well as in pharmacokinetics and toxicokinetics. Joseph [228] developed a biosensor with human CYP3A4 as a novel drugscreening tool. It was constructed by assembling enzyme films on Au electrodes by alternate adsorption of a layer of CYP3A4 on top of a layer of PDDA. The biosensor was applied to detect verapamil, midazolam, quinidine, and progesterone. 

A more recent example of this technique has been the study on human absorption characteristics of fexofenadine [109], Fexofenadine has been shown to be a substrate for P-gp in the in vitro cell lines its disposition is altered in knockout mice lacking the gene for MDRla, and co-administration of P-gp inhibitors (e.g. ketoconazole and verapamil) was shown to increase the oral bioavailability of fexofenadine [110-113], Hence, it is suggested that the pharmacokinetics of fexofenadine appears to be determined by P-gp activity. In the human model, the intestinal permeability estimated on the basis of disappearance kinetics from the jejunal segment is low, and the fraction absorbed is estimated to be 2% [114], Co-administration of verapamil/ketoconazole did not affect the intestinal permeability estimates however, an increased extent of absorption (determined by de-convolution) was demonstrated. The increased absorption of fexofenadine was not directly related to inhibition of P-gp-mediated efflux at the apical membrane of intestinal cells as intestinal Peff was unchanged. Furthermore, the effect cannot be explained by inhibition of intestinal based metabolism, as fexofenadine is not metabolised to any major extent. It was suggested that this may reflect modulation of efflux transporters in hepatocyte cells, thereby reducing hepatobiliary extraction of fexofenadine. 

Borlak J, Blickwede M, Hansen T, Koch W, Walles M, Levsen K (2005) Metabolism of verapamil in cultures of rat alveolar epithelial cells and pharmacokinetics after administration by intravenous and inhalation routes. Drug Metab Dispos 33(8) 1108-1114... 

Hepatic function impairment The pharmacokinetics, bioavailability and patient response to verapamil and nifedipine may be significantly affected by hepatic cirrhosis. 

Renal function impairment The pharmacokinetics of diltiazem and verapamil in patients with impaired renal function are similar to the pharmacokinetic profile of patients with normal renal function. However, caution is still advised. Nifedipine s plasma concentration is slightly increased in patients with renal impairment. Nicardipine s mean plasma concentrations, AUC and maximum concentration were about 2-fold higher in patients with mild renal impairment. 

Ho PC, Ghose K, Saville D, Wanwimolruk S. Effect of grapefruit juice on pharmacokinetics and pharmacodynamics of verapamil enantiomers in healthy volunteers. Eur J Clin Pharmacol 2000 56(9-10) 693-698. 

Zaidenstein R, Dishi V, Gips M, et al. The effect of grapefruit juice on the pharmacokinetics of orally administered verapamil. Eur J Clin Pharmacol 1998 54(4) 337-340. 

The pharmacokinetic properties of these drugs are set forth in Table 12-5. The choice of a particular calcium channel-blocking agent should be made with knowledge of its specific potential adverse effects as well as its pharmacologic properties. Nifedipine does not decrease atrioventricular conduction and therefore can be used more safely than verapamil or diltiazem in the presence of atrioventricular conduction abnormalities. A combination of verapamil or diltiazem with 3 blockers may produce atrioventricular block and depression of ventricular function. In the presence of overt heart failure, all calcium channel blockers can cause further worsening of heart failure as a result of their negative inotropic effect. Amlodipine, however, does not increase the mortality of patients with heart failure due to nonischemic left ventricular systolic dysfunction and can be used safely in these patients. 

Yasui-Furukori N, Uno T, Sugawara K, et al. Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics. Clin Pharmacol Ther 2005 77 17-23. 

Oral verapamil has been shown to increase peak plasma levels, prolong the terminal half-life, and increase the volume of distribution at steady state of doxorubicin (282). Gigante et al. (283) performed similar studies in which the pharmacokinetics of doxorubicin in combination with verapamil given at high doses intravenously were followed for 17 patients with advanced neoplasms. The steady-state concentration and systemic and renal clearances were found to be statistically similar for various doses of verapamil and doxorubicin, and for doxorubicin administered alone. 

Ince P, Elliott K, Appleton DR, et al. Modulation by verapamil of vincristine pharmacokinetics and sensitivity to metaphase arrest of the normal rat colon in organ culture. Biochem Pharmacol 1991 41(8) 1217-1225. 

Kerr DJ, Graham J, Cummings J, et al. The effect of verapamil on the pharmacokinetics of adriamycin. Cancer Chemother Pharmacol 1986 18(3) 239-242. 

Gigante M, Toffoli G, Boiocchi M. Pharmacokinetics of doxorubicin co-adminis-tered with high-dose verapamil. Br J Cancer 1995 71(1) 134—136. 

Pedersen KE. Digoxin interactions. The influence of quinidine and verapamil on the pharmacokinetics and receptor binding of digitalis glycosides. Acta Med Scand Suppl 1985 697 1-40. 

A third focus has been directed toward incorporation of conventional PET radionuclides nC or 18F into existing substrates or inhibitors known to interact with Pgp [113-115]. This strategy has been employed to produce various PET agents, including 1 -colchicine, 11C-verapamil, nC-daunomycin, and uC/18F-paclitaxel[115-123]. While promising data have been generated, some of these PET agents suffer from modest radiochemical yields and others from complex pharmacokinetics in vivo mediated, at least in part, by rapid metabolism of the radiolabeled compounds. 

Tsang, Y., Pop, R., Gordon, P., Hems, J., and Spino, M., High variability in drug pharmacokinetics complicates determination of bioequivalence Experience with verapamil, Pharmaceutical Research, Vol. 13, No. 6, 1996, pp. 846-850. 

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