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

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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‐1 h; P less than 0.05), bioavailability (R: 10.7 +/‐ 7.4%; S: 44.6 +/‐ 23.1%; P less than 0.05) and Cmax (R: 14.4 +/‐ 7.7; S: 72.5 +/‐ 40.5 ng ml‐1; P less than 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 contrast, 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‐1) of R‐ nitrendipine were doubled following R,S‐ as compared with R‐ nitrendipine administration. t1/2 (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 M1 were similar after administration of R‐ and S‐nitrendipine (S: 114.7 +/‐ 48.5; R: 71.7 +/‐ 29.9 ng ml‐1 h).(ABSTRACT TRUNCATED AT 250 WORDS)