Influence of plasma protein binding on the brain uptake of an antifungal agent, terbinafine, in rats.
The intracarotid injection technique has been used to determine the unidirectional brain uptake of an antifungal, lipophilic agent, terbinafine (Lamisil, Sandoz Basle), in the rat. Ultrafiltration showed it to be highly bound to human plasma, human serum albumin (HSA), alpha 1-acid glycoprotein (AAG) and lipoproteins (VLDL, LDL, HDL). The effect of plasma protein binding of the drug on brain uptake was also examined with the technique. The lowest brain uptake was observed in the presence of plasma (6%); it varied from 23 to 30% with physiological concentrations of VLDL, LDL and HSA and was significantly higher (43-45%) in the presence of physiological concentrations of AAG and HDL. The free fraction as determined in-vitro and the brain uptake of the drug varied inversely with the plasma protein concentrations; however, the brain uptake was higher than expected from in-vitro measurements. These data indicate that the amount of circulating Lamisil available for brain penetration exceeds its free fraction; they also show that plasma proteins differently reduce the brain transport of the drug.
Machard
B
B
Biopharmaceutical Department, Sandoz Ltd., Basle, Switzerland.
Misslin
P
P
Lemaire
M
M
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D006801:Humans; D008297:Male; D009281:Naphthalenes / Q000097:blood / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D000077291:Terbinafine
D001798:Blood Proteins; D009281:Naphthalenes; D000077291:Terbinafine