No Effect of High‐Protein Food on the Stereoselective Bioavailability and Pharmacokinetics of Verapamil

“…administration of VP (80 mg/kg) to healthy volunteers (Hashiguchi et al, 1996), corrected for the B/P ratio (Robinson and Mehvar, 1996), were 29 and 121 ng ⅐ h/ml, respectively, and the corresponding AUCs of the NVP enantiomers were 80 and 168 ng ⅐ h/ml. First-pass metabolism of VP in enterocytes has also been reported in humans (Sandström et al, 1999;von Richter et al, 2001).…”

Section: Stereoselective First-pass Metabolism Of Verapamilmentioning

confidence: 99%

“…The concentrations of the VP and NVP enantiomers in the plasma and blood were determined using a previously reported enantioselective HPLC method (Hashiguchi et al, 1996;Hanada et al, 1998a). The HPLC system consisted of a Shimadzu HPLC apparatus (Shimadzu, Kyoto, Japan), an LC-9A HPLC pump, and a C-R6A Chromatopac (Shimadzu) integrator.…”

mentioning

confidence: 99%

Stereoselective First-Pass Metabolism of Verapamil in the Small Intestine and Liver in Rats

Hanada¹,

Ikemi²,

Kukita³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Verapamil (VP) is used as a racemate but shows stereoselective pharmacokinetics and pharmacodynamics. It undergoes extensive first-pass metabolism. Stereoselective first-pass metabolism in the intestine and liver was investigated in vivo and in vitro to determine its impact on the disposition of VP and its main metabolite, norverapamil (NVP). VP racemate was administered to rats i.v., p.o., and via the portal vein. The formation rates of the main metabolites of the VP enantiomers were estimated in an in vitro intestinal microsomal study. The hepatic bioavailability of VP showed saturable metabolism, and the hepatic bioavailability of R-VP was higher than that of S-VP. Conversely, the intestinal bioavailability of R-VP was lower than that of S-VP, resulting in a higher systemic bioavailability of S-VP. The pharmacokinetics of the NVP enantiomers was similar. These results suggest that the stereoselectivity of the total bioavailability of VP is determined by first-pass metabolism in the small intestine and liver, and that the NVP enantiomers observed in the systemic circulation after p.o. administration of VP racemate originate mainly from the liver in rats.The first-pass metabolism of drugs in the small intestine and liver limits their bioavailability to the systemic circulation. Although the effects of first-pass metabolism in the liver after p.o. administration have been well studied, it is now known that many drugs also undergo first-pass metabolism in the small intestine. Reductions in the firstpass metabolism of these drugs, caused by drug-drug interactions or disease states, may occur to a different extent in the small intestine and liver. Therefore, it is very important to elucidate the mechanisms underlying first-pass metabolism, as well as the separate contributions of metabolism in the small intestine and liver, to be able to predict changes in oral bioavailability.Verapamil (VP) is a calcium antagonist used clinically for the treatment of hypertension and for prophylaxis of supraventricular and ventricular arrhythmias. VP has a relatively narrow therapeutic plasma concentration range and shows relatively large interindividual variations in its pharmacokinetics and pharmacodynamics (Vogelgesang et al., 1984;Echizen et al., 1985a Echizen et al., ,b, 1988. Although VP is commercially available as a racemic mixture, its pharmacological effects and disposition have been reported to show stereoselectivity in both humans and animals. The antiarrhythmic effect of S-VP, as estimated by electrocardiograph, is 10 to 20 times higher than that of R-VP in humans (Echizen et al., 1985a,b). The oral bioavailability of S-VP is approximately 20% in humans, whereas that of R-VP is approximately 50% (Vogelgesang et al., 1984;Echizen et al., 1985a Echizen et al., ,b, 1988. The plasma protein binding of R-VP is higher than that of S-VP (free fractions: 7 and 12%, respectively) (Gross et al., 1988;Robinson and Mehvar, 1996). We have previously reported that VP binds enantioselectively to ␣1-acid glycoprotein and ...

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“…8,9) The HPLC system consisted of a Shimadzu HPLC apparatus (Kyoto, Japan), a LC-9A HPLC pump and a C-R6A Chromatopac integrator. VP was detected by an RF-535 fluorescence detector which was operated at excitation and emission wavelengths of 272 and 312 nm, respectively.…”

Section: Methodsmentioning

confidence: 99%

Stereoselective Pharmacokinetics and Pharmacodynamics of Verapamil and Norverapamil in Rabbits.

Mori

Hanada

Mori

et al. 2001

Biological & Pharmaceutical Bulletin

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No Effect of High‐Protein Food on the Stereoselective Bioavailability and Pharmacokinetics of Verapamil

Cited by 11 publications

References 23 publications

Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: Verapamil hydrochloride, propranolol hydrochloride, and atenolol

Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: Verapamil hydrochloride, propranolol hydrochloride, and atenolol

Stereoselective First-Pass Metabolism of Verapamil in the Small Intestine and Liver in Rats

Stereoselective Pharmacokinetics and Pharmacodynamics of Verapamil and Norverapamil in Rabbits.

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