Use of pseudoracemic nitrendipine to elucidate the metabolic steps responsible for stereoselective disposition of nitrendipine enantiomers.

Abstract

1 The pharmacokinetics, protein binding, bioavailability and metabolism of (+)-R-and (-)-S-nitrendipine were studied in six healthy subjects following random oral administration of 20 mg (+)-R-, 20 mg (-)-S-and 20 mg R,S-nitrendipine (pseudoracemic mixture of 10 mg [13C4)-(+)-R-and 10 mg (-)-S-enantiomer). 2 After administration of the enantiomers pronounced differences in AUC (R: 29.9 + 20.1; S: 123.8 ± 63.7 ng ml-' h; P < 0.05), bioavailability (R: 10.7 ± 7.4%; S: 44.6 + 23.1%; P < 0.05) and Cmax (R: 14.4 ± 7.7; S: 72.5 ± 40.5 ng ml-1; P < 0.05) were observed between R-and S-nitrendipine. When racemic nitrendipine was given bioavailability and dose normalized AUC and Cmax values of the S-enantiomer were not different from the values after S-nitrendipine-administration. In constrast, bioavailability (R: 10.7% R,S: 22.1%) and dose normalized AUC (R: 15.0; R,S: 29.5 ng ml-1 h and Cmax (R: 7.2; R,S: 16.8 ng ml-') of R-nitrendipine were doubled following R,S-as compared with R-nitrendipine administration. t½/2 (R: 9.8; S: 9.1 h) and tmax were not different between the enantiomers nor were the values different after administration of the enantiomers or racemate. The fraction unbound in serum of R-nitrendipine was 0.0098 ± 0.0032 (s.d.) and that of S-nitrendipine was 0.0083 + 0.0015 (s.d.). 3 The AUC values of the major pyridine metabolite Ml were similar after administration of R-and S-nitrendipine (S: 114.7 ± 48.5; R: 71.7 ± 29.9 ng ml-' h). After racemic nitrendipine dose normalized AUC values were not different from those observed after administration of the enantiomers. 4 The cumulative urinary excretion of the four major pyridine metabolites M2a, M2b, M3a and M3b was significantly higher after S-nitrendipine. The % of dose which was recovered in urine within 48 h was 63.2 ± 6.6% (administration of racemate)/69.0 ± 5.9% (administration of S-enantiomer) for the S-enantiomer and 42.0 ± 5.1% (R,Snitrendipine)/43.8 ± 7.6% (R-enantiomer) for the R-enantiomer, respectively. Formation of metabolite M2a, which is generated by cleavage of the ethyl ester bond and oxidation of the 1,4-dihydropyridine ring to pyridine, exhibited stereoselectivity. On average 43.9 ± 3.9% of dose was formed from S-nitrendipine as compared with 24.7 ± 2.2% from R-nitrendipine following administration of the racemate. 5 Substantial differences in the metabolism, bioavailability and disposition of R-and Snitrendipine were observed. The first-pass metabolism of nitrendipine is stereoselective affecting mainly the less potent R-enantiomer. The bioavailability of R-nitrendipine doubled after administration of the racemate as compared with R-nitrendipine suggesting a metabolic enantiomer-enantiomer interaction with the S-enantiomer acting as an inhibitor of R-nitrendipine metabolism. With regard to the metabolic pathways responsible for stereoselective first-pass metabolism, it is unlikely that oxidation of nitrendipine to the pyridine metabolite Ml is involved since no substantial differences in the AUC of this metabolite were observed after admi...

Antihypertensive Drugs Metabolism: An Update to Pharmacokinetic Profiles and Computational Approaches

“…Nitrendipine is another dihydropyridine calcium channel blocker that follows a pattern of metabolism similar to nimodipine and nisodilpine. They all follow the oxidation of the dihydropyridine structure, hydroxylation to the methyl group and derivation of the corresponding carboxylic acids by the cleavage of the ester bonds [ 76 ].…”

Effect of bile acids on absorption of nitrendipine in healthy subjects

“…Previous studies have shown that the S‐enantiomer of nitrendipine is 7–8 times more potent than the R‐enantiomer [9]. In addition, the bioavailability of the S‐enantiomer is greater than that of the R‐enantiomer [10, 11]. Therefore, the measurement of plasma concentrations of these enantiomers separately may be relevant to our understanding of the clinical importance of the present drug interaction.…”