Pharmacokinetics of the Enantiomers of Verapamil After Intravenous and Oral Administration of Racemic Verapamil in a Rat Model

Bhatti, M. Masood; Foster, Robert T.

doi:10.1002/(sici)1099-081x(199707)18:5<387::aid-bdd26>3.0.co;2-x

Cited by 32 publications

(20 citation statements)

References 11 publications

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“…administration of VP racemate (Fig. 2), as has been reported previously (Bhatti and Foster, 1997). The oral clearance obtained at a dose of 5 mg/kg (S-VP 406, R-VP 936 ml/min/kg) was comparable with that at 10 mg/kg (S-VP 479, R-VP 965 ml/min/kg).…”

Section: Resultsmentioning

confidence: 99%

“…The F t of S-VP was higher than that of R-VP. This result was comparable with that reported by others (Bhatti and Foster, 1997). However, the F h of R-VP was almost double that of S-VP, whereas the F g of S-VP was higher than that of R-VP.…”

Section: Stereoselective First-pass Metabolism Of Verapamilmentioning

confidence: 99%

“…If S-VP is metabolized to a much greater extent than R-VP and the clearances of the NVP enantiomers are assumed to be the same, the AUC nvp for the S-isomer would be greater than that for the R-isomer. A similar relationship between VP and NVP is observed in rats, although the AUC vp and AUC nvp values for the S-isomer are greater than those for the R-isomer (Bhatti and Foster, 1997). These differences may be because of either stereoselective first-pass metabolism in the small intestine and liver or the disposition of NVP.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Stereoselective First-pass Metabolism Of Verapamilmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…Although the metabolism of verapamil is stereoselective (Nelson et al, 1988;Bhatti and Foster, 1997), its transport by P-gp is not (Luurtsema et al, 2003). For this reason and because our measure is brain/blood ratio of radioactivity, the use of the racemic verapamil does not in any way confound the interpretation of our data.…”

Section: Discussionmentioning

confidence: 99%

Verapamil P-glycoprotein Transport across the Rat Blood-Brain Barrier: Cyclosporine, a Concentration Inhibition Analysis, and Comparison with Human Data

Hsiao¹,

Sasongko²,

Link³

et al. 2006

J Pharmacol Exp Ther

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To predict the magnitude of P-glycoprotein (P-gp)-based drug interactions at the human blood-brain barrier (BBB), rodent studies are routinely conducted where P-gp is chemically inhibited. For such studies to be predictive of interactions at the human BBB, the plasma concentration of the P-gp inhibitor must be comparable with that observed in the clinic. Therefore, we determined the in vivo EC 50 of P-gp inhibition at the rat BBB using verapamil as a model P-gp substrate and cyclosporine A (CsA) as the model P-gp inhibitor. Under isoflurane anesthesia, male Sprague-Dawley rats were administered i.v. CsA to achieve pseudo steady-state CsA blood concentrations ranging from 0 to ϳ12 M. Then, an i.v. tracer dose of [ 3 H]verapamil was administered, and 20 min after verapamil administration, the animals were sacrificed for determination of blood, plasma, and brain 3 H radioactivity by scintillation counting. The percentage increase in the brain/blood 3 H radioactivity (relative to 0 M CsA) was described by the Hill equation with E max , 1290%; EC 50 , 7.2 M; and ␥, 3.8. Previously, using [11 C]verapamil, we have shown that the human brain/blood 11 C radioactivity was increased by 79% at 2.8 M CsA blood concentration. At an equivalent CsA blood concentration, the rat brain/blood 3 H radioactivity was increased by a remarkably similar extent of 75%. This is the first time that an in vivo CsA EC 50 of P-gp inhibition at the rat BBB has been determined and the magnitude of such inhibition was compared between the rat and the human BBB at the same blood CsA concentration.

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“…These enantiomers have different pharmacodynamic and pharmacokinetic properties (Lankford and Bai, 1995;Mateus et al, 2007;Pagel et al, 1998;Bhatti and Foster, 1997;Robinson and Mehvar, 1996). S-(-)-VER has negative chronotropic and inotropic effects, delays atrioventricular node conduction and causes systemic and coronary artery vasodilatation.…”

Section: Ver Is a Chiral Drug That Is Administered As A Racemic Mixtumentioning

confidence: 99%

Chromatographic Separation of Verapamil Racemate Using a Varicol Continuous Multicolumn Process

Cremasco

Santana²

2015

Braz. J. Chem. Eng.

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-Verapamil is a chiral drug that is marketed in its racemic form, but because of the pharmacological effects due to molecule's chirality, one of the enantiomers is more potent, and the other exhibits different activities of therapeutic interest. The preparative separation of the verapamil enantiomers was performed using a continuous Varicol unit operated on a scale of 1 g/day. Amylose tris(3,5-dimethylphenylcarbamate) functioned as the stationary phase, and n-hexane/isopropanol/ethanol mixtures were used as the mobile phase. Diethylamine was used as the additive. The enantiomeric purities were 93.0% for S-(-)-verapamil and 92.0% for R-(+)-verapamil in the raffinate and extract streams, respectively. The unit provided productivities of 0.18 kg of raffinate per day per kg of adsorbent and 0.20 kg of extract per day per kg of adsorbent when using a feed concentration of 12.5 g L -1 .

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Pharmacokinetics of the Enantiomers of Verapamil After Intravenous and Oral Administration of Racemic Verapamil in a Rat Model

Cited by 32 publications

References 11 publications

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

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

Verapamil P-glycoprotein Transport across the Rat Blood-Brain Barrier: Cyclosporine, a Concentration Inhibition Analysis, and Comparison with Human Data

Chromatographic Separation of Verapamil Racemate Using a Varicol Continuous Multicolumn Process

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