Verapamil bioavailability

This chapter reviews the pharmacokinetics and pharmacodynamics of the enantiomers of verapamil and examines their impact on verapamil bioavailability. In addition, new information on the influence of product formulation on the differential bioavailabiUty of the enantiomers of verapamil is presented and discussed. 

Barbarash RA, Bauman JL, Fischer JH, Kondos GT, Batenhorst RL. Near-total reduction in verapamil bioavailability by rifampin. Electrocardiographic correlates. Chest 1988 94(5) 954-9. 

Schwarz, U. I., Gramatte, T., Krapp-weis, J., Berndt, A., Oertel, R., von Richter, O., Kirch, W., Unexpected effect of verapamil on oral bioavailability of the beta-blocker talinolol in humans, Clin. Pharmacol. Ther. 1999, 65, 283-290. 

An additional example of a bioavailability-predicted absorption plot is shown for a series of calcium antagonists (Fig. 19.8). Again there is considerable scatter in the data, and the four compounds - felodipine, nisoldipine, diltiazem, and verapamil -are predicted to be much better absorbed than was actually observed. Some of these compounds are known to undergo rapid first-pass metabolic clearance, and are also P-gp inhibitors or substrates (diltiazem and felodipine are P-gp substrates nicardipine and nitrendipine are P-gp inhibitors [25] verapamil is a P-gp inhibitor), and this might contribute to the scatter obtained in the graph. 

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. 

In contrast to P-gp and the MRP proteins, the breast cancer resistance protein (BCRP) contains six transmembrane domains and only one ATP-binding domain. It was first cloned from the breast cancer cell line MCF-7 selected in doxombicin, in the presence of the P-gp inhibitor verapamil. It is found in many human tissues, such as the placenta, small intestine, colon, and liver [133], It is localized to the apical membrane of epithelial cells of the small intestine and colon and to the bile canalicular membrane in the liver and is involved in reducing intestinal uptake, increasing hepatobiliary excretion, etc., leading to diminished oral bioavailability. cDNA sequences identical to BCRP and named MXR and ABCP, respectively, were independently isolated from human colon carcinoma cells and human placenta [134], BCRP requires... 

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

It was determined that 95% of an oral 80-mg dose of verapamil was absorbed in a 70-kg test subject. However, because of extensive biotransformation during its first pass through the portal circulation, the bioavailability of verapamil was only 25%. Assuming a liver blood flow of 1500 mL/min, the hepatic clearance of verapamil in this situation was 60 mL/min 375 mL/min 740 mL/min 1110 mL/min 1425 mL/min... 

Tannergren C, Engman H, Knutson L, Hedeland M, Bondesson U, Lennernas H. St John s wort decreases the bioavailability of R- and S-verapamil through induction of the first-pass metabolism. Clin Pharmacol Therapeut 2004 75(4) 298-309. 

Dofetilide is 100% bioavailable. Verapamil increases peak plasma dofetilide concentration by increasing intestinal blood flow. Eighty percent of an oral dose is eliminated by the kidneys unchanged the remainder is eliminated in the urine as inactive metabolites. 

The half-life of verapamil is approximately 7 hours. It is extensively metabolized by the liver after oral administration, its bioavailability is only about 20%. Therefore, verapamil must be administered with caution in patients with hepatic dysfunction. 

Gum formulations containing caffeine showed rapid release and absorption of the agent with comparable bioavailability to the capsule form [57], Various gum formulations with vitamin C [56], diphenhydramine [58], methadone [59], and verapamil [60] have been developed and tested. 

Christrup, L.L., et al. 1990. Relative bioavailability of (+/—)-verapamil hydrochloride administered in tablets and chewing gum. Acta Pharm Nord 2 371. 

Dofetilide is 100% bioavailable. Verapamil increases peak plasma dofetilide concentration by increasing intestinal blood flow. Eighty percent of an oral dose is eliminated by the kidneys unchanged the remainder is eliminated by the kidneys as inactive metabolites. Inhibitors of the renal cation secretion mechanism, eg, cimetidine, prolong the half-life of dofetilide. Since the QT-prolonging effects and risks of ventricular proarrhythmia are directly related to plasma concentration, dofetilide dose must be based on the estimated creatinine clearance. Treatment with dofetilide should be initiated in hospital after baseline measurement of the QTc and serum electrolytes. A baseline QTC of > 450 ms (500 ms in the presence of an intraventricular conduction delay), bradycardia of < 50 beats/min, and hypokalemia are relative contraindications to its use. 

In view of their incomplete oral bioavailability, several CYP2C substrates may undergo significant first-pass intestinal metabolism, including the CYP2C9 substrates verapamil (155), losartan (156), fluvastatin (157), and diclofenac (158), and the CYP2C19 substrates (5)-mephenytoin (159) and omeprazole... 

Eichelbaum, M., Dengler, H. J., Somogyi, A., and von Unruh, G. E. (1981). Superiority of stable isotope techniques in the assessment of the bioavailability of drugs undergoing extensive first pass elimination. Studies on the relative bioavailability of verapamil tablets. Eur. J. Clin. Pharmacol. 19, 127-131. 

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