Clinical Pharmacokinetics of Lercanidipine

Abstract

(±) Lercanidipine hydrochloride (HCl) (Zanidip) is an antihypertensive drug structurally related to dihydropyridine calcium-entry blockers: lercanidipine is weakly basic (pK′a = 6.83 at 37°C) and highly lipophilic (log P octan-1-ol/water = 6 at 20-25°C). After oral administration of 10-20-mg lercanidipine HCl tablets, absorption is practically complete and peak plasma concentration (Cmax) is observed within 3 h. Area under the curve (AUC) and Cmax are linearly but more than proportionally correlated with the dose. The plasma concentration profile of lercanidipine enantiomers is similar; AUC and Cmax values for the S(+), the eutomer for antihypertensive activity, are on average 1.2 times those of R(−). Distribution from plasma to tissues and organs is rapid (t1/2α = 20 min) and extensive. The apparent volume of distribution is in the range of 2-2.5 L/kg. More than 98% of the drug is bound to human plasma proteins. Elimination occurs essentially by biotransformation. The absolute availability of lercanidipine is relatively low as a consequence of high first-pass metabolism; no parent drug is found in the urine or feces. Plasma half-life is about 2-5 h. The principal biotransformation pathways of lercanidipine in humans involve aromatization of the heterocyclic ring, hydroxylation of the β-carbon atom on the 1,1-dimethylethyl-substituted ester function leading to loss of the N-methyl-N-(3.3-diphenyl)propylamine side-chain, nitro reduction, N,N-didealkylation, and O-glucuronidation. all of which are well-documented biotransformations of related dihydropyridines such as the structurally similar analogue nicardipine. Elderly subjects and subjects with hepatic failure (cirrhotic, class A on the Child-Pugh scale) do not require dosage adjustment. For subjects with severe renal insufficiency, a reduction of the daily dose is advisable. Some interaction with food is observed when lercanidipine HCl is administered with a high-fat meal. No interaction is observed with cimetidine and digoxin. Lercanidipine has one of the highest measured membrane partition coefficients for any calcium antagonist to date. This behavior supports the long-lasting pharmacologic activity observed.