title: Effects of trimethoprim on the clearance of apricitabine, a deoxycytidine analog reverse transcriptase inhibitor, and Lamivudine in the isolated perfused rat kidney.
abstract: Apricitabine (ATC) is a novel deoxycytidine analog reverse transcriptase inhibitor in development for the treatment of human immunodeficiency virus infection. Studies were performed to characterize the excretion of ATC and its metabolite, BCH-335 (-1-(2-hydroxymethyl-[1,3]oxathiolan-4-yl)-1H-pyrimidine-2,4-dione), in the isolated perfused rat kidney (IPK). A second objective was to investigate the effect of trimethoprim on ATC excretion because trimethoprim inhibits the excretion of lamivudine, structurally similar to ATC, in the IPK. ATC excretion was nonlinear at doses of 80 to 1600 microg. The excretion ratio (ratio of clearance to glomerular filtration rate, assuming negligible protein binding) was greater than 1.0, indicating net tubular secretion. In contrast, the excretion of BCH-335 was independent of the dose of BCH-335. Concomitant administration of ATC and BCH-335 did not affect the excretion of either compound. Trimethoprim significantly inhibited the excretion of both ATC and BCH-335, with IC(50) values of 0.45 and 0.54 microg/ml, respectively. In the presence of trimethoprim, the excretion ratios for both compounds were less than 1.0, indicating tubular reabsorption. Trimethoprim inhibited the excretion of ATC and lamivudine to similar extents. Following concomitant administration of ATC, lamivudine, and trimethoprim, there was no evidence of an interaction between ATC and lamivudine. These results suggest that ATC undergoes active tubular secretion in the kidney. Because the renal excretion of both ATC and lamivudine is inhibited by trimethoprim to similar extents, in clinical practice exposure to ATC, it would be expected to be increased in the presence of therapeutic concentrations of trimethoprim to a similar extent as has been shown previously for lamivudine.
authors.affiliation: Division of Pharmaceutical Sciences, Long Island University, 75 DeKalb Avenue, Brooklyn, NY 11201, USA.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nakatani-Freshwater
authors.forename: Mariana
authors.initials: M
authors.lastname: Babayeva
authors.forename: Aruna
authors.initials: A
authors.lastname: Dontabhaktuni
authors.forename: David R
authors.initials: DR
authors.lastname: Taft
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D004347:Drug Interactions; D007668:Kidney / Q000378:metabolism*; D019259:Lamivudine / Q000493:pharmacokinetics*; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics*; D014295:Trimethoprim / Q000494:pharmacology*
chemical_list: D000890:Anti-Infective Agents; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; D019259:Lamivudine; D014295:Trimethoprim; C508042:apricitabine