Lamivudine undergoes minimal metabolism and renal clearance of the unchanged drug is the predominant mechanism of clearance. The effect of trimethoprim on the renal clearance of lamivudine was investigated in rats in-vivo. Total renal clearance of lamivudine was about three times higher than the glomerular filtration rate in rats receiving an infusion of tritium-labelled lamivudine. Concomitant infusion of trimethoprim reduced the renal clearance of lamivudine to about half, but did not affect the level of radioactivity in the renal cortex. When rats received an infusion of lamivudine with probenecid, cimetidine or quinidine, the renal clearance of lamivudine was only significantly reduced by co-administration of cimetidine. These findings suggest that secretion in the renal proximal tubule takes an active part in the total renal clearance of lamivudine, and that cationic drugs such as trimethoprim and cimetidine may inhibit the secretion of lamivudine without greatly affecting the concentration of lamivudine in the renal cortex.