Separation of Two Conjugates of Clofjbric Acid (Cpib) Found in the Urine of Subjects Taking Clofibrate

Faed, Ellen M.; McQueen, E. G.

doi:10.1111/j.1440-1681.1978.tb00671.x

Cited by 29 publications

(15 citation statements)

References 9 publications

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“…Acyl (ester) glucuronides have been reported to be unstable at neutral and basic environments, undergoing possible intramolecular acyl migration and direct hydrolysis (Smith et al, 1985;Benet, 1992, 1993;Bailey and Dickinson, 2003). The common degradation products of positional isomers of glucuronic acid formed by acyl migration are generally resistant to cleavage by ␤-glucuronidase, a commonly used reagent employed in studies of glucuronides (Faed and McQueen, 1978;Hasegawa et al, 1982;Spahn-Langguth and Benet, 1992;Bailey and Dickinson, 2003). Since PA-457, a triterpenne derivative, is a poor UV chromaphore, it is difficult to analyze by chromatographic assay with UV detection.…”

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confidence: 99%

Structural Characterization of Anti-HIV Drug Candidate PA-457 [3-O-(3′,3′-Dimethylsuccinyl)-betulinic acid] and Its Acyl Glucuronides in Rat Bile and Evaluation of in Vitro Stability in Human and Animal Liver Microsomes and Plasma

Zhao

Stern

Martin³

et al. 2006

Drug Metab Dispos

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ABSTRACT:PA-457 [3-O-(3,3-dimethylsuccinyl)-betulinic acid] represents a new class of anti-HIV drug candidates termed maturation inhibitors. After oral administration to rats, PA-457 was metabolized to several glucuronide conjugates and mainly eliminated into rat bile. Liquid chromatography-electrospray ionization-mass spectrometry analysis showed that the glucuronidation products of PA-457 were acyl glucuronides including one di-glucuronide, di-PA-457G, and two mono-glucuronides, referred to as mono-PA-457G (I) and mono-PA-457G (II), respectively. In-source fragmentation of MS spectra supported the conclusion that mono-PA-457G (I) was glucuronidated at the C-28 carboxyl of PA-457, whereas mono-PA-457G (II) was conjugated at the dimethylsuccinic acid side chain of the C-3 position. Quantification demonstrated that the predominant glucuronide of PA-457 in rat bile was mono-PA-457G (I) with lower amounts of mono-PA-457G (II) and di-PA-457G. In vitro stability indicated that the mono-acyl glucuronides of PA-457 were not degraded after incubation with 0.1 M phosphate buffer (pH 4, 7.4 and 9), plasma (human, rat, and mouse), and UDP-glucuronosyltransferase reaction media (without uridine 5-diphosphoglucuronic acid) with microsomes (human, rat, and mouse liver microsomes), respectively, whereas the minor diglucuronide was unstable in rodent liver microsomes. All glucuronides of PA-457 could be hydrolyzed both by ␤-glucuronidase and alkaline (1 M NaOH). Minor putative acyl migration products were slowly formed at pH 9, suggesting that the acyl glucuronides of PA-457 have relatively high in vitro stability.

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confidence: 99%

Structural Characterization of Anti-HIV Drug Candidate PA-457 [3-O-(3′,3′-Dimethylsuccinyl)-betulinic acid] and Its Acyl Glucuronides in Rat Bile and Evaluation of in Vitro Stability in Human and Animal Liver Microsomes and Plasma

Zhao

Stern

Martin³

et al. 2006

Drug Metab Dispos

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“…We have previously found that this conjugate accounts for a variable fraction (27-74%, mean 57.4%, n = 85) of the conjugated CPIB in urine (Faed & McQueen, 1978).…”

Section: Discussionmentioning

confidence: 98%

“…We have previously shown that urine contains two main conjugates of clofibric acid, only one of which is susceptible to hydrolysis by the enzyme 0-glucuronidase (Faed & McQueen, 1978). Using TLC it was found that the metabolites of clofibric acid in plasma were similar to those in urine (Fig.…”

Section: Comparison Of Cpib Metabolites In Plasma and Urinementioning

confidence: 93%

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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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“…C]pivaloylglycine and [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]pivaloylcarnitine hydrochloride were synthesized by a reaction of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]pivaloylchloride with glycine and carnitine, respectively, as illustrated in Fig. 2.…”

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Disposition of S-1108, a new oral cephem antibiotic, and metabolic fate of pivalic acid liberated from [pivaloyl-14C]S-1108 in rats and dogs

Mizojiri

Futaguchi

Norikura

et al. 1995

Antimicrob Agents Chemother

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[pivaloyl-14 C]S-1108, which is 14 C labeled at the pivalic acid moiety of the pivaloyloxymethyl side chain of S-1108, was administered orally to rats and dogs, and the disposition of pivalic acid cleft from S-1108 was examined. Besides pivaloylcarnitine and pivaloylglucuronide, pivaloylglycine was identified in dog urine as a metabolite of pivalic acid by thin-layer chromatography and high-performance liquid chromatography analysis. The concentrations in the plasma of rats to which doses of 6.65, 26.6, and 532 mg/kg of body weight were administered showed dose-proportionate levels. The radioactivity was eliminated rapidly, with a half-life of approximately 3 h until 24 h at both the 6.65-and 26.6-mg/kg doses. Free pivalic acid in plasma accounted for more than 80% of the concentration of radioactivity. Radioactivity was distributed throughout the body and was eliminated quickly at a rate similar to that of radioactivity from plasma. Most of the absorbed radioactivity was excreted in the urine, and it was completed within 24 h after administration. In dogs, the half-life of radioactivity in plasma was longer than that in the rats. The ratio of free pivalic acid in plasma was 60 to 70% of the radioactivity in plasma. The concentration of radioactivity in the liver, cortex of the kidney, and skeletal muscle 144 h after oral dosing was more than 10 times higher than the concentration in plasma for all doses. Urinary excretion in dogs was slower than that in rats. The differences in the disposition of pivalic acid between dogs and rats may account for differences in the degree of skeletal muscle disorders. The safety in humans of S-1108 given at 200 mg three times a day is discussed in relation to the metabolic formation of the carnitine conjugate of pivalic acid and the reduction of the carnitine concentration in plasma.S-1108 is a new oral cephem antibiotic and is a prodrug of S-1006 (12); the absorbability of S-1006 increases by esterification of the carboxy group at the C-4 position of the cephem ring with pivaloyloxymethyl (POM). S-1108 is hydrolyzed to the active moiety, S-1006, and components of the ester residue, formaldehyde and pivalic acid, by an esterase in the gut wall.

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Separation of Two Conjugates of Clofjbric Acid (Cpib) Found in the Urine of Subjects Taking Clofibrate

Cited by 29 publications

References 9 publications

Structural Characterization of Anti-HIV Drug Candidate PA-457 [3-O-(3′,3′-Dimethylsuccinyl)-betulinic acid] and Its Acyl Glucuronides in Rat Bile and Evaluation of in Vitro Stability in Human and Animal Liver Microsomes and Plasma

Structural Characterization of Anti-HIV Drug Candidate PA-457 [3-O-(3′,3′-Dimethylsuccinyl)-betulinic acid] and Its Acyl Glucuronides in Rat Bile and Evaluation of in Vitro Stability in Human and Animal Liver Microsomes and Plasma

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

Disposition of S-1108, a new oral cephem antibiotic, and metabolic fate of pivalic acid liberated from [pivaloyl-14C]S-1108 in rats and dogs

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