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 μg. 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 IC50 values of 0.45 and 0.54 μg/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.
Footnotes
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This work was supported by Avexa Ltd. (Richmond, Australia).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.108522.
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ABBREVIATIONS: ATC, apricitabine, (–)-2′-deoxy-3′-oxa-4′-thiocytidine; HIV, human immunodeficiency virus; BCH-335, –1-(2-hydroxymethyl-[1,3]oxathiolan-4-yl)-1H-pyrimidine-2,4-dione; IPK, isolated perfused rat kidney; GFR, glomerular filtration rate; LC-MS/MS, liquid chromatography with mass spectrometry; BCH-4556, troxacitabine; XR, excretion ratio; AUC, area under the concentration time curve.
- Received May 26, 2006.
- Accepted August 21, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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