Pharmacokinetics of nilvadipine, a new dihydropyridine calcium antagonist, in mice, rats, rabbits and dogs

Abstract

1. The pharmacokinetics of nilvadipine in male and female rats, and in male mice, rabbits and dogs were studied after i.v. and oral dosing. 2. After i.v. dosing (0.1 mg/kg), the plasma concentrations of nilvadipine declined two- or three-exponential with terminal half-lives of 0.73 h in mice, 1.2 h in male and female rats, 3.7 h in rabbits and 5.0 h in dogs. Sex difference in pharmacokinetics after i.v. dosing in rats was not found. The systemic plasma clearance was in the order of mice greater than rats greater than rabbits greater than dogs, and nearly equalled the hepatic blood flow in each species. The volume of distribution at steady-state was high (greater than 4 L/kg) in all species. 3. After oral dosing, plasma concentrations of nilvadipine peaked within 1 h in all species except for middle and higher doses (4 and 16 mg/kg) in dogs. The area under the plasma concentration-time curves in male rats (3.2-100 mg/kg) and dogs (1-16 mg/kg) increased in proportion to the dose. Bioavailability was low in male rats (3-4%) and rabbits (2%), but in other species was 29-44%. The oral clearance in male rats was about 8 times higher than in female rats. 4. The free fraction of nilvadipine in plasma was 1.94% in mice, 1.89% in rabbits and 0.85% in dogs, with no dependence on plasma concentration over a range of 10-100 ng/ml.

A Review on Barnidipine: A Novel Calcium Antagonist

“…1 h in the dog) (9) or benidipine (0.5 and 1 . 1 to 1.5 h) (15); they were similar to nisoldipine (0.4 and 4.0 h) (I), nitrendipine (1.3 and 1.8 h) (17), felodipine (1.5 and 4.2 h) (2), or nilvadipine (1.3 and 5.0 h) (44). Amlodipine, a 1,4-dihydropyridine calcium antagonist, however, displayed a longer half-life in rats (3 h) and dogs (30 h) (37).…”

Pharmacokinetics of mebudipine, a new calcium antagonist, following single intravenous and oral administrations in rats

“…In fact, the mebudipine plasma concentration declined biexponentially. The plasma concentration of most dihydropyridines have shown bi or tri exponential decline [8,10,11,12,13]. Therefore, it is concluded that mebudipine is pharmacokinetically similar to other dihydropyridines.…”

“…The systemic clearance of most dihydropyridines is equal to or higher than the liver blood flow [10,11]. Benidipine [8], nisoldipine [12], nitrendipine [13], felodipine [8], nilvadipine [11] and lacidipine [10] have a higher systemic clearance than mebudipine after intravenous administration. When considering the CL of 1.67 l/h/kg, the systemic clearance of mebudipine is generally high and it seems that the main reason for the long half-life of mebudipine is a large volume of distribution (6.2 l/kg).…”

“…The mean oral bioavailability of mebudipine was 1.77%, being very low and similar to the oral bioavailability of nilvadipine (4.3%) [11], barnidipine (11%-18%) [8], nitrendipine (11%) [13], nisoldipine (3.4%) [12] and benidipine (3.1%) [15] in rats. Regardless of complete absorption from the GI tract, the extensive first-pass effect is a common property of dihydropyridines such as nicardipine, nisoldipine, felodipine, nilvadipine and lacidipine [10].…”

Factors Affecting the Absorption of Nilvadipine from Disintegration-Controlled Matrix Tablet in Dogs

“…17,18) Although these reports suggested that NiD was highly permeable drug in upper bowel, the permeability in distal bowel has not been clarified. Thus, regional difference in intestinal absorption of NiD was evaluated in dogs using in situ closed loop, by obtaining the decrease of NiD concentration in solution from duodenal, jejunal, ileal, and colonic loops.…”