Purine Arabinosides as Inhibitors of Human Haemopoietic Progenitor Cells

Averett, Devron R.; Steinberg, Howard; Koszalka, George W.; Spector, Thomas; Krenitsky, Thomas A.

doi:10.1177/095632029200300308

Cited by 3 publications

(4 citation statements)

References 15 publications

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“…In addition, enzyme studies have shown that ara-M is a substrate for ADA, yielding ara-H as its product (3). High levels of ADA in the intestines of rats, as well as other animals (14), would expose ara-M to this enzyme during absorption and, therefore, could explain the marked difference in the extent of ara-M metabolism after intravenous and oral dosing.…”

Section: Discussionmentioning

confidence: 99%

“…One group of orally dosed rats was treated with EHNA (50 mg/kg; intraperitoneally) at 1 h predose and at 3 and 6 h postdose, and the other group was not pretreated. Blood samples were obtained from each animal at 2, 5, 10, 20, 40, and 60 min and 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, and 6.0 h postdose. Blood samples (0.4 to 0.5 ml) were withdrawn through the cannula into syringes containing EDTA.…”

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confidence: 99%

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Metabolic disposition and pharmacokinetics of the antiviral agent 6-methoxypurine arabinoside in rats and monkeys

Burnette

Koszalka

Krenitsky

et al. 1991

Antimicrob Agents Chemother

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The metabolism and pharmacokinetics of 6-methoxypurine arabinoside (ara-M), a potent and selective inhibitor of varicella-zoster virus, were investigated in rats and monkeys. In Long Evans rats, orally administered [8-'4CIara-M (10 mg/kg) was well absorbed but extensively metabolized to hypoxanthine arabinoside (ara-H), hypoxanthine, xanthine, uric acid, and allantoin. Only 4% of an oral dose was recovered in the urine as unchanged drug, compared with 40% of an intravenous dose, indicating significant presystemic metabolism. Pretreatment of rats with 1-aminobenzotriazole, an inhibitor of cytochrome P-450, did not alter this metabolism. Pretreatment with deoxycoformycin or erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride, inhibitors of adenosine deaminase, resulted in a marked decrease in ara-M metabolism, indicating that adenosine deaminase plays a major role in the biotransformation of ara-M. In cynomolgus monkeys, [8-'4C]ara-M (10 mg/kg) administered intravenously or orally was extensively metabolized to ara-H. Several minor urinary metabolites were detected in both rats and monkeys. However, adenine arabinoside was not found in urine or plasma from either rats or monkeys after administration of ara-M, except for a very low level detected in the urine of rats pretreated with deoxycoformycin. The elimination half-lives of intravenously administered ara-M in rats and monkeys were 29 and 45 min, respectively. The corresponding half-lives of the primary metabolite, ara-H, were 44 min and 2.3 h. Plasma profiles of orally administered ara-M in both rats and monkeys demonstrated the poor oral bioavailabifity of this arabinoside. The results of these studies indicate that ara-M is not well suited for oral administration because of extensive presystemic metabolism.Recently, a series of 6-alkoxypurine arabinosides was demonstrated to have activity against varicella-zoster virus (VZV) in vitro (2). In that series of compounds, 6-methoxypurine arabinoside (ara-M) was the most potent. In addition, ara-M was more potent than the agents used clinically for the treatment of herpes zoster, acyclovir (ZOVIRAX) and adenine arabinoside (ara-A; Vidarabine) (28). ara-M is an efficient substrate for VZV-encoded thymidine kinase (2) and undergoes highly selective anabolism in VZV-infected human foreskin and lung fibroblasts (4,8).This paper describes the metabolism and pharmacokinetics of ara-M in two animal models, Long Evans rats and cynomolgus monkeys. These studies were conducted to aid in evaluating the in vivo suitability of this arabinoside as an anti-VZV agent.MATERIALS AND METHODS Chemicals. ara-M was synthesized at Wellcome Research Laboratories as reported previously (2). [8-'4C]ara-M (49 Ci/mol) was prepared by combining 26.6 mg of [8-14C]6-methoxypurine (56 Ci/mol; Wizard Laboratories, Davis, Calif.) in 1 ml of 95% ethanol with 0.15 g of uracil arabinoside and 8 ml of 10 mM potassium phosphate (pH 7.4).Escherichia coli uridine phosphorylase (153 U) and purine nucleoside phosphorylase (PNP) (277 U) were added. The react...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Metabolic disposition and pharmacokinetics of the antiviral agent 6-methoxypurine arabinoside in rats and monkeys

Burnette

Koszalka

Krenitsky

et al. 1991

Antimicrob Agents Chemother

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“…Enzyme and in vivo studies indicate that adenosine deaminase catabolizes 1 to hypoxanthine arabinoside, which is then excreted or further metabolized (Averett et al, 1991b;Burnette et et., 1991). A significant first-pass effect was indicated by the dramatic differences in urinary recovery of unchanged 1 following oral and intraperitoneal administration (Burnette et al, 1991).…”

Section: -Methoxypurine Arabinoside (9-[i3-d-arabinofuranosyl]mentioning

confidence: 99%

5′Prime;-Ester Prodrugs of the Varicella-Zoster Antiviral Agent, 6-Methoxypurine Arabinoside

Chamberlain

Moorman

Jones

et al. 1992

Antivir Chem Chemother

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SummaryThe potent and selective activity of 6-methoxypurine arabinoside (9B[I3-D-arabinofuranosyl]-6-methoxy-9H-purine; 1) and its pharmacokinetic limitations have been described previously. In an attempt to circumvent first-pass catabolism following oral administration, a series of 5 ' -esters (2a-t) was prepared by dicyclohexyl-carbodiimide-promoted condensation with formic acid in the case of 2a, or by direct acylation of the parent nucleoside with the corresponding acyl chloride. These compounds were evaluated in rats for efficacy as oral prodrugs of 1 by measuring the amount of 1 excreted in the urine. Both aliphatic and aromatic esters exhibited a range of systemic availabilities. The substituted benzoate esters showed a correlation between the amount of 1 excreted and the electron-donating properties of the substituent. A similar relationship was observed for the relative stabilities of this series of esters to non-enzymatic hydrolysis at neutral pH. No clear relationship between systemic availability and solubility, partition coefficient, or stability was observed for the remaining esters of 1. Although significant enhancements in systemic availability were observed with some of the 5 ' -esters of this series, their limited water solubility precluded their use in intravenous formulations.

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“…This arabinoside is metabolized by adenosine deaminase to hypoxanthine arabinoside (Averett et al, 1991b), which in turn, can undergo phosphorolysis to hypoxanthine and arabinose-1-phosphate by the action of purine nucleoside phosphorylase (Stoeckler et el., 1980). Both of these catabolic reactions are rather sluggish in vitro compared to the action of these enzymes on their natural nucleoside substrates.…”

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2-Ester Prodrugs of the Varicella-Zoster Antiviral Agent, 6-Methoxypurine Arabinoside

Chamberlain

Moorman

Jones

et al. 1992

Antivir Chem Chemother

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Summary 6-Methoxypurine arabinoside [9-([3-D-arabinofuranosyl)-6-methoxy-9H-purine; 1] is a potent and selective agent against varicella-zoster virus in vitro. Studies in the rat indicated that extensive first pass metabolism of this nucleoside occurred after oral dosing, presumably from high levels of adenosine deaminase in the intestine. Only 3.8% of an oral dose of 6-methoxypurine arabinoside was recovered in the urine. In an attempt to improve these unfavourable pharmacokinetics, a series of twenty-five 2'-esters of 6-methoxypurine arabinoside were prepared either by direct acylation or by a protection, acylation, and deprotection sequence. These esters were evaluated in the rat for their suitability as prodrugs on the basis of urinary recovery of 1 after oral dosing. The straightchain aliphatic esters, but not the branched chain or aromatic esters, improved this urinary recovery. Thẽ '-valerate, hexanoate, heptanoate, and octanoate esters (2d-g, respectively) were the most effective, with urinary recoveries of 1 above 15%. The water solubility ofthe valerate ester was high (107 mM at 37°C and pH 7.2), but .solubilities progressively decreased with the longer chain esters. The combination of high water solubility and improved metabolic stabilitY, upon oral dosing made 2d the prodrug of choice for both oral and intravenous dosing.

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Purine Arabinosides as Inhibitors of Human Haemopoietic Progenitor Cells

Cited by 3 publications

References 15 publications

Metabolic disposition and pharmacokinetics of the antiviral agent 6-methoxypurine arabinoside in rats and monkeys

Metabolic disposition and pharmacokinetics of the antiviral agent 6-methoxypurine arabinoside in rats and monkeys

5′Prime;-Ester Prodrugs of the Varicella-Zoster Antiviral Agent, 6-Methoxypurine Arabinoside

2-Ester Prodrugs of the Varicella-Zoster Antiviral Agent, 6-Methoxypurine Arabinoside

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