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, 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 g. 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 g/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.Apricitabine (ATC; Fig. 1; previously referred to as SPD754 and AVX754) is a novel deoxycytidine analog reverse transcriptase inhibitor that is undergoing clinical development for the treatment of human immunodeficiency virus (HIV)-1 infection (Taylor et al., 2000;Cahn et al., 2006). Pharmacokinetic studies in healthy volunteers have shown that this agent is eliminated primarily by renal excretion of unchanged drug. After oral administration, 65 to 80% of the dose is excreted unchanged in the urine after 24 h (Holdich et al., 2006). ATC undergoes conversion in vivo (Ͻ10% of administered dose) to an inactive metabolite, BCH-335. The most likely metabolic pathway for the generation of BCH-335 is metabolism in the bowel by normal intestinal flora (Avexa Limited, personal communication). Given the structural similarity between ATC and BCH-335 (Fig. 1), it is likely that both compounds are excreted by similar mechanism(s).Studies using the isolated perfused rat kidney (IPK) model suggested that the renal clearances of ATC and BCH-335 were reduced when the two compounds were applied to the perfusate concomitantly (D. R. Taft, unpublished observations). The reason for this finding is unclear. Decreased clearance of ATC in the presence of its metabolite would be consistent with a ...

Renal excretion of apricitabine in rats: ex vivo and in vivo studies

“…The IC 50 value of trimethoprim for inhibition of ATC excretion was 0.5 lg/mL in the IPK (Nakatani-Freshwater et al 2006). The value was substantially lower than the plasma concentrations achieved with doses of trimethoprim used in the treatment of HIV infection.…”

“…This included characterization of the renal excretion of ATC in vivo, and further evaluation of potential drug-drug interactions identified in previous IPK studies ( ATC-trimethoprim;Nakatani-Freshwater et al 2006), and the present investigation (ATC-cimetidine, and ATC-metformin).…”

“…2.0 mL/min) respectively, when ATC was co-administered with cimetidine in vivo. Likewise, trimethoprim co-administration decreased ATC clearance by 78% in the IPK (Nakatani-Freshwater et al 2006) compared to\40% in vivo (Table 4).…”

“…The renal excretion of ATC has previously been evaluated using the isolated perfused rat kidney (IPK) model (Nakatani-Freshwater et al 2006). The study demonstrated that ATC undergoes active tubular secretion in the IPK, and co-administration of trimethoprim significantly reduced ATC renal clearance.…”

Molecular Pharmacology of Nucleoside and Nucleotide HIV-1 Reverse Transcriptase Inhibitors

“…The intracellular halflife is 6 -7 hours (Sawyer & Struthers-Semple, 2006;Cahn et al, 2008;Holdich et al, 2007). Apricitabine is not metabolized by hepatocytes in vitro, however a deaminated metabolite was observed likely due to gastrointestinal metabolism (Nakatani-Freshwater et al, 2006). This metabolite is excreted renally and does not demonstrate antiviral or pharmacologic effects.…”