Barnidipine

Barnidipine (pure S,S isomer) is a lipophilic 1,4-dihydropyridine calcium antagonist showing high affinity for the calcium channels of the smooth muscle cells in the vascular wall. Receptor kinetics of barnidipine are characterised by a slow onset of action and a strong and long-lasting binding. The reduction in peripheral resistance brought about by barnidipine results in blood pressure lowering. When using barnidipine, the antihypertensive effect remains during the entire 24-hour dose interval.

Use of barnidipine in chronic treatment does not lead to an increase in basic heart frequency. The impact of barnidipine on cardiovascular morbidity or mortality has not been studied. However, recently completed, controlled studies of other long acting dihydropyridines indicate similar beneficial effects on morbidity and mortality compared to other antihypertensives in hypertension of the elderly.

Metabolic effects

Barnidipine does not exert any negative effect on serum lipids profile, glucose level or blood electrolytes.

Absorption

After repeated administration of barnidipine to healthy individuals, the concomitant intake of food did not have a statistically significant effect on AUC, C_max, Tmax or t½. Maximum plasma levels are obtained 5 to 6 hours after oral administration of barnidipine. Barnidipine shows an absolute bioavailability of 1.1%. Barnidipine plasma concentrations may show considerable interpersonal variation.

Distribution

In vitro studies show that barnidipine binds at the rate of 26-32% to human erythrocytes and to a high extent (89-95%) to plasma proteins. In vitro analysis of protein components indicates that barnidipine mainly binds to serum albumin, followed by α1 acid glycoprotein and high density lipoproteins. To a much lesser extent binding to γ-globulin takes place. No drug interactions based on elimination of plasma protein binding have been observed in in-vitro studies.

Biotransformation

Barnidipine is to a great extent metabolised into inactive metabolites. No in vivo chiral inversion of the pure S,S isomer takes place. Main reactions are N-debenzylisation of the side chain, hydrolysis of the Nbenzylpyrrolidine ester, oxidation of the 1,4-dihydropyridine ring, hydrolysis of the methyl ester and reduction of the nitro group. The metabolism of barnidipine seems mainly mediated by the CYP3A isoenzyme family.

Elimination

The median terminal elimination plasma half-life of barnidipine was 20 hours after repeated administration, according to a two-compartment analytical model. Elimination mainly takes place through metabolism. Barnidipine and/or its metabolites are excreted in faeces (60%), urine (40%) and breath (less than 1%). No unmetabolised barnidipine is excreted in urine.

Special patient groups

After a single dose, barnidipine plasma levels are 3 to 4 times higher in patients with mild to moderate hepatic impairment than in healthy volunteers. The variability in plasma levels is also increased. Barnidipine plasma levels are on average twice as high in patients with renal impairment not needing haemodialysis than in healthy volunteers. The average plasma level in patients needing haemodialysis is more than 3 times as high as in healthy volunteers, accompanied by increased variability.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.