RENAL DISPOSITION AND DRUG-INTERACTION SCREENING OF (-)-2'-DEOXY-3'-THIACYTIDINE (3TC) IN THE ISOLATED-PERFUSED RAT-KIDNEY

Purpose. Dideoxynucleoside bases are used for the treatment of acquire d immune deficiency syndrome (AIDS), acting by inhibiting reverse tran scriptase and preventing human immunodeficiency virus (HIV) replicatio n. Currently, AZT (zidovudine), ddC (zalcitibine), and ddI (didanosine ) are available to the medical community to prevent the onset of AIDS in HIV-infected individuals. 3TC (-)-2'-deoxy-3'-thiacytidine, lamivud ine), a new dideoxynucleoside base, is currently undergoing Phase II/I II trials, and has exhibited anti-HIV replication activity, a favorabl e adverse event safety profile, and is eliminated via renal mechanisms . Concomitantly administered drugs could potentiate the effects of 3TC due to interaction in the kidney. Methods. An isolated perfused rat k idney (IPK) technique was used to screen several clinically relevant d rugs for potential interaction with 3TC. The following perfusions were performed: baseline 3TC; and 500 ng/mL 3TC with clinically relevant c oncentrations of AZT, ddC, ddI, probenecid, trimethoprim, sulfamethoxa zole, ranitidine, and cimetidine. Results. Renal clearance of 3TC was nonlinear between 500 and 5000 ng/mL, decreasing from 3.06 to 1.74 mL/ min. Excretion ratio also decreased, from 3.67 (500 ng/mL) to 2.49 (50 00 ng/mL), consistent with a decrease in 3TC secretion. AZT, ddI, and ddC elicited no or minimal effects on 3TC elimination at the concentra tions studied. However, trimethoprim caused significant reductions in 3TC elimination parameters: clearance and excretion ratio decreased to 1.25 mL/min and 1.43, respectively. Conclusions. These results indica te that caution should be exercised when the combination of 3TC and tr imethoprim are administered to AIDS patients.