Verapamil oral administration, racemate

Talinolol, a good P-gp substrate, is eliminated from the body mainly by intestinal and renal excretion with minimal metabolism in humans. In a clinical study, a P-gp-mediated interaction between talinolol and verapamil has been reported (45). The inhibitory effect of verapamil on the intestinal secretion of talinolol was determined in six healthy volunteers by using the intestinal perfusion technique. While perfusing the small intestine with a verapamil-free solution, the mean intestinal secretion rate of talinolol was 4.0 pg/min after an intravenous dose of talinolol. The intestinal secretion rate decreased to 2.0 pg/min when a verapamil-containing solution was perfused (45). Similar to the clinical data, talinolol-verapamil interaction was also observed in rats. Coadministration of verapamil (4 mg/kg, PO) resulted in a 2.5- and 2.2-fold increase in the plasma oral AUC for S- and //-talinolol, respectively, after an oral dose of racemic talinolol in rats. On the other hand, after an intravenous dose of racemic talinolol, the inhibitory effect of verapamil on talinolol was less significant and there was only a 40% and 30% increase in AUC, respectively, for S- and //-talinolol (46). These results suggest that the larger increase in AUC of talinolol ( 2- to 2.5-fold) after oral administration was likely due to the combination of an... 

Figure 4 Mean it-verapamil S-verapamil ratio observed following intravenous and oral dosing of racemic verapamil. A, After intravenous administration of a single 15 mg dose in 8 volunteers (personal communication from A. Rasymas, Univ. of Toronto, Canada). B, After oral administration of two different 120-mg immediate release formulations dosed every 8 hr to 22 normal volunteers in a crossover design study and measured at steady state over two dosing intervals (- -, test formulation u, reference formulation). C, After oral administration of two different lots of a 180-mg once daily sustained-release formulation to 48 normal volunteers in a cross-over design study and measured at steady state new manufacturing site n, reference manufacturing site).

It has been suggested [60,61] that the rate of input of chiral drugs after the oral administration may affect the stereoselectivity in their pharmacokinetics. Simulations [60] have shown that drugs with Michaelis-Menten type first-pass metabolism whose input rate approaches the maximum rate of metabolism (Fmax) of the enantiomers are most susceptible to this phenomenon. A study [151] in isolated perfused rat livers demonstrated that when the input rate of racemic verapamil was doubled, the stereoselectivity in the outlet concentration of the drug was lost. In humans, Karim and Piergies [152] showed that the R S plasma concentration ratios of verapamil at maximum plasma concentration (Cmax) were formulation dependent a sustained release formulation resulted in lower total concentrations at time to reach C ax ( max), associated with higher R S ratios, when compared with an immediate release formulation (Fig. 8). Similar input rate-dependent stereoselective pharmacokinetics of verapamil have also been suggested by others [146,153]. 

Many beta-blockers and calcium channel blockers are administered orally as racemates, and they have high oral absorption but low systemic availabihty of the active moiety owing to high hepatic first-pass metabolism (see Chap. 7 for more detail). If there is high enantioselective first-pass metabolism, and if the enantiomers have different pharmacological characteristics, then the PK/PD study to evaluate the relationship between plasma concentration and response, when a nonspecific assay is used, will depend on the route of drug administration. This phenomenon occurs with racemic propranolol [37 2] and verapamil [43 54]. 

The whole sample was then injected onto the chiral column, 10 cm long, 4.0 mm I.D., packed with silica gel particles, 5 pm in diameter, bonded with a,-acid glycoprotein (AGP). The results obtained are shown in figure 11.2. The separation ratio between the enantiomer pair is 1.23. Chromatogram (A) is the separation of a 50 ng sample of the racemic pair. Chromatogram (B) is from a blood serum sample taken 4 hours after the oral administration of 120 mg of racemic Verapamil. Chromatogram (C) is from a blood serum sample taken 15 min after the intravenous infusion of 15 mg of racemic Verapamil. It is clear that this type of analysis will allow an accurate pharmokinetic study of the relative biochemical degradation or excretion of the two enantiomers. 

Verapamil provides an example of the importance of the stereoselectivity of a drug in a biological system, since verapamil is used as a racemic mixture of the pharmacologically active (-) enantiomer and the non-active (-F) enantiomer. Verapamil undergoes stereoselective first pass metabolism after oral administration and the bioavailability of the active (-) form is 2-3 foldless than the non-active (-F) form thus... 

A classic method of demonstrating enantioselective first-pass metabolism is to administer the racemic drug orally and i.v. in a crossover study and then evaluate the PK of each enantiomer using a stereospecific assay. Stereoselective first-pass metabolism is indicated by significantly different absolute bioavailabilities of the enantiomers. This approach was used to establish low enantioselective first-pass metabolism of ketoprofen [56] and high enantioselectivity of propranolol [38,42] and verapamil [44,45,53]. Enantioselective metabolism of propranolol and verapamil has been studied extensively and found to be influenced by age and gender [40,50]. With verapamil, changes in plasma enantiomeric ratios after administration... 

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