Metabolism and pharmacokinetics of the dihydropyridine calcium antagonist, ryosidine, in man

Abstract

1. The metabolic fate of [¹⁴C]ryosidine (ryodipine) has been investigated after oral administration to human subjects (by capsule), and to rats and dogs (in solution). The excretion patterns of ¹⁴C were similar for all three species: about 50% dose was excreted in urine, mainly in 24 h, but a proportion was excreted slowly, particularly by humans. Absorption in man appeared to be less than in the animal species, probably as a result of the capsule dosage form used.

1 μg equiv./ml at four hours and declined biphasically thereafter (mean terminal t_1/2 = 28 h). Unchanged ryosidine was only detected in plasma from two to six hours (mean t_1/2 = 80 min), and never accounted for more than 5% of the plasma ¹⁴C. The extent of binding of ryosidine to the plasma proteins (in vitro) was similar (>90%) to that of total ¹⁴C (in vivo; mainly metabolites).

2. Mean concentrations of total ¹⁴C in human plasma reached a peak value of 0·4

3. Less than 0·5% of the dose to human subjects was excreted via the kidneys as unchanged ryosidine, whereas the bulk of the extractable faecal ¹⁴C was in the form of unchanged drug and presumably represented unabsorbed material. The principal routes of biotransformaiion of ryosidine in all three species involved oxidative aromatization of the 1,4-dihydropyridine ring, followed by ester hydrolysis, O-dealkylation, hydroxylation of an α-methyl group (and lactonization) and some glucuronidation, although quantitative inter-species differences were apparent.