Chemistry of D-Glucuronic Acid and Its Glycosides

Marsh, C. A.

doi:10.1016/b978-0-12-395501-2.50007-4

Cited by 16 publications

(7 citation statements)

References 586 publications

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“…1 istration of 60 mg/kg are illustrated in Fig. 2 21 to 95%. The time to reach peak FDT concentrations in serum was also variable, with the peak occurring between 15 min and 1.5 h. The CSF/FDT concentration ratio in serum was independent of the route of administration, averaging 0.14 ± 0.03.…”

Section: Resultsmentioning

confidence: 99%

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

Schinazi

Boudinot

Doshi

et al. 1990

Antimicrob Agents Chemother

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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.

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Section: Resultsmentioning

confidence: 99%

“…The concentrations of D4T and FDT glucuronide in urine were determined after the glucuronate was hydrolyzed with P-glucuronidase (21). To 100 ,u of urine were added 15 pl of 0.12 N acetic acid, 100 pul of P-glucuronidase (500 U/ml in water), and 35 plI of phosphate buffer, pH 5.8.…”

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confidence: 99%

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

Schinazi

Boudinot

Doshi

et al. 1990

Antimicrob Agents Chemother

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“…The concentrations of FTC and FTU glucuronides in urine were determined after the glucuronate was hydrolyzed with 3-glucuronidase (16). To 100 p.l of urine were added 15 p,l of 0.12 N acetic acid, 100 p1l of 3-glucuronidase (500 U/ml in water), and 35 pl of phosphate buffer, pH 5.8.…”

mentioning

confidence: 99%

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

Schinazi

Boudinot

Ibrahim

et al. 1992

Antimicrob Agents Chemother

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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.

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“…Ester glucuronides are unstable in only slightly alkaline solution (Marsh, 1966) and this may have contributed to the failure of previous workers to detect CPIB metabolites in plasma or serum. Care must be taken in the handling of samples because breakdown of the conjugates can occur at room temperature.…”

Section: Discussionmentioning

confidence: 99%

Measurement of Clofibric Acid (Cpib) Metabolites in Plasma of Patients on Clofibrate Therapy

Faed

McQueen

1979

Clin Exp Pharmacol Physiol

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1. The metabolites of clofibric acid [CPIB;2-(chlorophenoxy)-2-methylpropionic acid] are present in the plasma of patients on clofibrate therapy. The highest plasma concentrations of CPIB in metabolite form (up to 51 micrograms/ml) were generally found in patients with renal disease. Negligible concentrations (less than or equal to 2 micrograms/ml) were found in only seven patients out of thirty-six studied. 2. The two conjugates of CPIB found in urine were present in plasma. 3. When measuring conjugated CPIB in plasma it is essential to take care in the handling and storage of specimens, and to select an assay method known to be specific for unmetabolized CPIB.

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Chemistry of D-Glucuronic Acid and Its Glycosides

Cited by 16 publications

References 586 publications

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

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

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

Measurement of Clofibric Acid (Cpib) Metabolites in Plasma of Patients on Clofibrate Therapy

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