Pharmacokinetics of Lercanidipine in Animals

Abstract

The absorption and excretion of (±)3,5-pyridinedicarboxilic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethyl ethyl methyl ester hydrochloride (lercanidipine hydrochloride; Zanidip) have been mainly studied after administration of the 14C-labeled compound to rats and dogs at the “no toxic effect” dose of 3 mg/kg and in rabbits and in mice at higher doses. Studies after repeated p.o. and i.v. administration have also been performed. After a single p.o. dose of lercanidipine HCl in rats, the absolute bioavailability of total radioactivity and of the parent drug were 47 and 17% respectively. Availability of lercanidipine was similar after single and repeated p.o. administration for both sexes. Unlike humans, rats exhibited plasma concentrations of the (R)-enantiomer higher than those of the (S)-enantiomer, the S/R ratio being 0.25. The mass balance of 14C at 120 h post dose was practically complete after both single and repeated p.o. administration, for which a modest drug accumulation (mean accumulation factor of 1.5) was seen. In dogs, after a single p.o. dose of lercanidipine HCl, the absolute availability of the radioactivity was 61% and that of lercanidipine was 3-5%. Its S/R enantiomeric ratio was about 2.3, similar to that observed in humans. No gross differences between sexes and no accumulation after repeated treatment (mean accumulation factor of 0.8) were observed. The decay of radioactivity in plasma was biexponential, the mean half-lives being 2.7 and 36 h, respectively. The mass balance of14C at 120 h post dose was about 12% of the dose in the urine and 78% in the feces after both single and repeated p.o. administration. In mice, after 1 mg/kg i.v. or 10 and 100 mg/kg p.o., the absolute availability of radioactivity was 66% of the dose at 10 mg/kg and 49% at 100 mg/kg. Unchanged lercanidipine accounted for 9% of total radioactivity in plasma after i.v. administration and 1.6 and 2.5% after 10 and 100 mg/kg p.o. administration, respectively. Absolute availability of oral lercanidipine was 11 and 13%, respectively. The mass balance of 14C up to 96 h post dose was practically complete after i.v. and p.o. administration. Excretion of radioactivity in the urine and in the feces accounted for 18% and 78% of the dose, respectively. In female rabbit, after 4 mg/kg i.v. or 50 and 500 mg/kg p.o., the absolute availability of radioactivity was about 6.5% for both p.o. doses. Unchanged lercanidipine accounted for 5.5% of total radioactivity after i.v. and 0.26% after 500 mg/kg p.o. administration. Absolute availability of the higher oral dose was only 0.3%. Unchanged drug profile at 50 mg/kg dose could not be defined owing to the low levels obtained. Radioactivity was completely recovered in 120-h urine and feces after both i.v. and p.o. administration.