Pharmacokinetics of 3'-fluoro-3'-deoxythymidine and 3'-deoxy-2',3'-didehydrothymidine in rhesus monkeys

Abstract

nucleoside analogs which inhibit human and simian immunodeficiency virus in vitro. The pharmacokinetic properties of these compounds in rhesus monkeys after intravenous, oral, and subcutaneous administration of the drug were compared. Half-lives, total clearances, and steady-state volumes of distribution for the two drugs were determined. The half-lives for the drugs by the different routes were between 0.58 and 1.4 h. Oral bioavailabllity of 3'-deoxy-2',3'-didehydrothymidine was incomplete, with an average of 42% ± 15% of the dose reaching the systemic circulation. Absorption of 3'-fluoro-3'-deoxythymidine after oral administration was variable, with bioavailability ranging from 21 to 95%. Bioavailability after subcutaneous administration ranged from 59 to 77% for 3'-deoxy-2',3'-didehydrothymidine and from 52 to 59% for 3'-fluoro-3'-deoxythymidine. The ratio of concentrations in cerebrospinal fluid and serum for the drugs was about 0.15 at 1 h after drug administration and was independent of the route of administration, suggesting that a nucleoside carrier-mediated process is involved in the transport of these compounds to the central nervous system. Because of the similar metabolism of nucleoside analogs in monkeys and humans, the potential glucuronide formation was assessed. Whereas the glucuronide of 3'-fluoro-3'-deoxythymidine was readily detected in urine, the amount of 3'-deoxy-2',3'-didehydrothymidine glucuronidated was small or not detectable in one-half of the urine samples. Pharmacokinetic parameters for the two drugs were similar to each other and analogous to those for 3'-azido-3'-deoxythynidine in monkeys, suggesting that the same dose and scheduling of the drug can be used for all three compounds in prophylactic and therapeutic efficacy drug studies in rhesus monkeys.

The transport of the anti‐HIV drug, 2′,3′‐didehydro‐3′‐deoxythymidine (D4T), across the blood‐brain and blood‐cerebrospinal fluid barriers

“…However, the rate of entry of [ 3 H]-AZT into the CSF, as determined by multiple-time point analysis, was 0.77+0.16 ml min 71 g 71 and was found not to be signi®cantly di erent than that obtained for [ 3 H]-D4T. This agrees with data from a clinical trial in children (Kline et al, 1995) and laboratory based studies in adult rhesus monkeys and adult and infant macaques (Schinazi et al, 1990;Keller et al, 1995), which have shown that D4T and AZT enter the CSF to a similar extent.…”

“…The octanol-saline partition coe cient determined for [ 3 H]-D4T was 0.167 and a similar value of 0.11 has previously been reported (Schinazi et al, 1990). The hydrophilic control, D-[ 14 C]-mannitol, mainly partitioned in the saline phase yielding a partition coe cient of 0.002.…”

“…However, the passage of these nucleoside analogues across the blood-CSF barrier would appear to be independent of lipophilicity and, since the uptake of D4T and AZT was found not to be saturable (Figure 2; Thomas & Segal, 1997a), further suggests that their CSF entry is via the paracellular route. Schinazi et al (1990) also found that penetration of D4T and AZT into simian CSF was independent of lipophilicity. However, they suggested that this was due to the transport of the compounds via a carrier-mediated process.…”

Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism

“…In a study using monkeys and isolated rat hepatocytes, the degradation of stavudine was detected in thymine (12) and the d4T-TP derivative, with subsequent production of beta aminoisobutyric acid (BAI-BA) (13) (Cretton et al, 1993). The glucuronide metabolite (14) of stavudine was found in the urine of monkeys but has remained controversial (Schinazi, et al, 1990).A recent study reported by our group (Freitas, 2009) described the metabolic profile of stavudine, applying in vivo, in vitro and in silico approaches. The bioconversion experiments with nine strains of filamentous fungi, detected one major metabolite, which was further identified as thymine (12).…”

“…Liver-derived HepG-2 and BC2 cell lines and lung-derived line A549 have the disadvantage of expressing few enzymes, restricting their metabolic capacity (Yoshitomi et al, 2001;Le Vee et al, 2006). However, the recent human hepatoma-derived cell line HepaRG has been shown to possess functions and morphological resemblance to normal human hepatocytes (Aninat et al, 2006).The use of microorganisms as models of mammalian metabolism was introduced in the early 1970s by Smith and Rosazza (Smith, Rosazza, 1974, 1975. This method uses eukaryotic microorganisms to produce metabolites similar to mammals, since microbial transformation systems could closely mimic most of the Phase I transformations of drugs observed in mammals, mainly those catalyzed by cytochrome P450 (Azerad, 1999).…”