In-vitro distribution of terbinafine in rat and human blood

The association of drugs with plasma lipoproteins has the potential to influence drug action and disposition. In this study, the uptake and distribution of the lipophilic antifungal drug, terbinafine, was investigated in rat and human blood and plasma. Fresh plasma was incubated with terbinafine (200-1000 ng mL(-1)), then subjected to vertical spin density gradient ultracentrifugation to separate protein fractions. The concentrations of terbinafine in each fraction was determined using a validated reversed-phase HPLC method. The association of terbinafine with very-low-density lipoproteins (15.5 +/- 7.1% of total concentration) in human plasma was significantly lower than that associated with fractions containing soluble proteins (28.0 +/- 6.2%), high- (26.8 +/- 7.7%) and low-density lipoproteins (31.6 +/- 4.6%). In rats terbinafine was found to be distributed evenly through plasma protein fractions. The association of terbinafine in lipoproteins was independent of concentration (over the range 200-1,000 ng mL(-1)) and species. The distribution of terbinafine was examined in human and rat blood and the blood-to-plasma ratio of terbinafine was 0.70+0.09 and 1.01 +/- 0.20, respectively, indicating higher association of terbinafine with plasma components than erythrocytes in humans. This study suggests that in humans and rats, terbinafine associates with a number of plasma proteins independently of terbinafine concentration. Alteration in plasma lipoprotein concentrations are therefore likely to influence terbinafine binding in blood and distribution in the body.