Pharmacokinetics and metabolism of racemic 2',3'-dideoxy-5-fluoro-3'-thiacytidine in rhesus monkeys

Abstract

2',3'-Dideoxy-5-fluoro-3'-thiacytidine (FTC) is a nucleoside analog that selectively inhibits human immunodeficiency and hepatitis B viruses in vitro. In this study, the preclinical pharmacokinetics of racemic FTC in rhesus monkeys following intravenous and oral administration were characterized. The terminal half-life of FTC was independent of the route of administration and averaged 1.34 ± 0.18 h (mean ± standard deviation). Total clearance of FTC was moderate to high, averaging 1.49 ± 0.24 liters/h/kg. Qualitative assessment of urine samples suggests that renal excretion of unchanged FTC was the major route of elimination of the nucleoside. The compound was also eliminated by metabolism and the deaminated biotransformation product 2,3'-dideoxy-5-fluoro-3'-thiauridine (FT]U) was detected in serum and urine. This metabolite has no antiviral activity in human lymphocytes and liver cells. FTC and the metabolite FTU were conjugated, to a minor extent yielding the corresponding glucuronides. No 5-fluorouracil was detected in serum or urine. This is consistent with chromatographic studies using a chiral column that indicated that when racemic FTC is treated with cellular cytidine-deoxycytidine deaminase, the D-(+)-enantiomer of FTC is slowly deaminated to D-(+)-FTU, whereas the L-(-)-enantiomer is essentially resistant to this enzyme. The steady-state volume of distribution of FTC in serum averaged 2.23 ± 0.42 liters/kg, and the nucleoside analog was distributed into the cerebrospinal fluid, which suggests that this drug penetrated the blood-brain barrier. Absorption of FTC after oral administration was rapid, with bioavailabiity averaging 73 ± 6%. Taken together, the results indicate that the unusual L-(-)-enantiomer of FTC should be evaluated further in rhesus monkeys prior to determination of whether this compound is useful for treatment of human immunodeficiency and hepatitis B virus infections.

Magnetic resonance spectroscopy reveals that activated monocytes contribute to neuronal injury in SIV neuroAIDS

“…To investigate the role of plasma virus and monocyte activation/ infection in CNS neuronal injury, we treated 2 SIV-infected, CD8 lymphocyte-depleted animals with CART beginning 28 days after infection, once we had confirmed by MRS significant decreases in NAA/Cr. CART consisted of treatment with PMPA and RCV (75,76). PMPA is a nucleotide analog that does not penetrate the CNS, and RCV is a nucleoside analog of a class that has low-to-nondetectable CNS penetration (40,(77)(78)(79).…”

“…Animals received daily injections of PMPA (30 mg/ kg) and RCV (10 mg/kg) s.c. Plasma and CSF specimens taken before and after initiation of CART were stored at -80°C, and RCV metabolites were analyzed by HPLC, as previously described (76).…”

Resting CD4 + T Lymphocytes but Not Thymocytes Provide a Latent Viral Reservoir in a Simian Immunodeficiency Virus- Macaca nemestrina Model of Human Immunodeficiency Virus Type 1-Infected Patients on Highly Active Antiretroviral Therapy

“…The other two animals (98P009 and 97P021) were not given any drugs and served as no-therapy controls. PMPA is a nucleotide RT inhibitor that does not cross the brain-blood barrier (1,18), and FTC is a nucleoside RT inhibitor that crosses the blood-brain barrier (46).…”

Safety, Pharmacokinetics, and Efficacy of (+/−)-β-2′,3′-Dideoxy-5-Fluoro-3′-Thiacytidine with Efavirenz and Stavudine in Antiretroviral-Naïve Human Immunodeficiency Virus-Infected Patients

“…Interestingly, studies have shown that they select for different mutations on the HIV-1 reverse transcriptase gene in vitro, M184V for the (Ϫ) enantiomer and T215Y for the (ϩ) enantiomer (9,10). In addition these same studies showed that time to emergence of resistant virus in peripheral blood mononuclear cell culture was prolonged with RCV (14 weeks) compared to either lamivudine (3TC) (9 weeks) or (Ϫ)-FTC (9 weeks) (7,8; R. F. Schinazi, personal communication). This could be advantageous for a therapeutic regimen if the emergence of resistance mutations in patients were also delayed.…”

“…A major advantage of using RCV would be that the virus would be challenged with two different compounds, which should increase the difficulty of developing resistance to both enantiomers (10). Both enantiomers are well absorbed orally and have demonstrated low toxicity in preclinical safety studies (1,2,3,4,8).…”