Environmental degradation of the miticide cycloprate (hexadecyl cyclopropanecarboxylate). 4. Beagle dog metabolism

Quistad, Gary B.; Staiger, Luana E.; Schooley, David A.

doi:10.1021/jf60215a010

Cited by 28 publications

(6 citation statements)

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“…Metabolites other than the carnitine conjugate were glucuronide and glycine conjugates, as reported in the cycloproate studies of animals (14)(15)(16). In our related study of S-1108 metabolism in dogs, these three conjugates were identified as the major metabolites of PA in urine.…”

Section: Concentrations In Plasma Concentrations Of S-1006 Totalsupporting

confidence: 66%

Metabolism of S-1108, a new oral cephem antibiotic, and metabolic profiles of its metabolites in humans

Totsuka¹,

Shimizu²,

Konishi³

et al. 1992

Antimicrob Agents Chemother

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The metabolism and pharmacokinetics of pivalic acid, a major metabolite of S-1108, were studied with three healthy volunteers. Concentrations of S-1006 (the active compound), pivalic acid, and pivaloylcarnitine in plasma and urine were measured after administration of S-1108. Recoveries in urine at the doses of S-1108 given (100 and 200 mg) were 33 to 41% for S-1006, 93% for total pivalic acid, and 89 to 94% for pivaloylcarnitine in 24 h, and maximum concentrations in plasma were 2 ,ug of S-1006 per ml, 1 ,ug of total pivalic acid per ml, and 2 ,ug of pivaloylcarnitine per ml after a 200-mg oral administration of S-1108. More than 90% of the pivalic acid was excreted as pivaloylcarnitine, and no measurable amount of free pivalic acid was present in urine samples, indicating that the pivalic acid liberated from S-1108 was almost quantitatively conjugated with carnitine in the human body. The level of free carnitine in plasma was unaffected by a single 200-mg administration of S-1108, whereas urinary excretion of free carnitine decreased as levels of acylcarnitine increased. The acylcarnitines were excreted primarily in the form of pivaloylcarnitine. This study clearly showed how the pivalic acid was metabolized and excreted in humans. The importance of monitoring carnitine, an essential cofactor in fatty acid metabolism, was also discussed in terms of its utilization by pivalic acid.S-1108, an oral cephem antibiotic, is a prodrug of S-1006 (4a). S-1108 is hydrolyzed by an esterase in the intestinal tracts of humans to produce S-1006, pivalic acid (PA), and formaldehyde in a manner similar to that of other prodrugs having a pivaloyloxymethyl (POM) ester (3,6,18). The metabolic and pharmacokinetic profiles of S-1108 have been intensively studied, including clinical evaluations (12a, 18a). Furthermore, an investigation of the metabolism of PA was needed to confirm the biological profile of the POM ester type of prodrug. The metabolism of PA has been studied by Vickers et al. (19), who found that pivaloylcarnitine (PC) was its major urinary metabolite when the POM ester derivative of methyldopa was given to humans. Since then, PC has been found to be the common metabolite of prodrugs that possess the POM ester group in their chemical structures (5,9,10). Carnitine is an essential cofactor in fatty acid

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Section: Concentrations In Plasma Concentrations Of S-1006 Totalsupporting

confidence: 66%

Metabolism of S-1108, a new oral cephem antibiotic, and metabolic profiles of its metabolites in humans

Totsuka¹,

Shimizu²,

Konishi³

et al. 1992

Antimicrob Agents Chemother

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“…CPCA, which is the best substrate for in vitro carnitine conjugation in all animals examined, was excreted mainly into urine as the major metabolite of carnitine conjugate with a minor metabolite of glycine conjugate following administration at 20 mg kg −1 of cycloprate to dogs (Quistad et al 1978c), suggesting good agreement with in vitro data of dogs (Table 2). On the other hand, the major urinary metabolite of CPCA was glycine conjugate with a small amount of carnitine conjugate following administration of cycloprate at 20 mg kg −1 to rats (Quistad et al 1978a), which showed some discrepancy with earlier findings (Kanazu & Yamaguchi 1997).…”

Section: Discussionsupporting

confidence: 72%

“…Therefore, the carnitine conjugate is considered to be part of one of the important metabolic pathways of carboxylic acid compounds. However, there are few reports concerning the carnitine conjugate for exogenous compounds, except those for cyclopropanecarboxylic acid (Quistad et al 1978a(Quistad et al , 1978b(Quistad et al , 1978c and valproic acid (Millington et al 1985). We have conducted some in vitro studies on the metabolism of PA analogues using rat tissues and found some interesting information on substrate specificity, such as that cyclic carboxylic acids with lower carbon numbers are good substrates for carnitine conjugate, but glycine conjugates show inversed specificity (Kanazu & Yamaguchi 1997).…”

Section: Introductionmentioning

confidence: 99%

Substrate specificity for carnitine and glycine conjugation of branched side-chain and cyclic side-chain carboxylic acids in various experimental animals

Kanazu

Yamaguchi

2009

Xenobiotica

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Substrate specificities for the carnitine and glycine conjugates of branched side-chain and cyclic side-chain carboxylic acids were examined using dog, rabbit, cynomolgus monkey, and squirrel monkey hepatocytes and kidney slices. For all tested samples, the substrate specificity for carnitine or glycine conjugation showed a similar tendency to those for rat experiments reported previously, that is, the best substrate for the carnitine conjugate was cyclopropanecarboxylic acid (CPCA), while that for the glycine conjugate was benzoic acid (BA), followed by cyclohexanecarboxylic acid (CHCA). With respect to carnitine conjugation for CPCA, rat hepatocytes showed the highest ability followed by dog, rabbit, and monkey hepatocytes. Rat kidney slices showed the highest carnitine conjugation ability, followed by rabbit, dog, and monkey kidney slices, in that order. With respect to glycine conjugation for BA, rabbit hepatocytes showed the highest ability, followed by rat and monkey hepatocytes. Dog hepatocytes have no or little glycine conjugate ability for the carboxylic acids studied here. Rabbit kidney slices showed the highest glycine conjugation ability followed by rat, dog, and monkey kidney slices.

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“…The role of carnitine in the conjugation and -oxidation pathways of acidic xenobiotics has been well documented [15,16]. For example, the carnitine conjugates of cyclopropane carboxylic acid have been observed in rats [17] and dogs [18]. Pivalic acid (formed from a methyl dopa prodrug) is also converted to a carnitine conjugate in humans [19], as is valproic acid [20].…”

Section: Discussionmentioning

confidence: 99%

Disposition of Vorinostat, A Novel Histone Deacetylase Inhibitor and Anticancer Agent, in Preclinical Species

Sandhu¹,

Andrews²,

Baker³

et al. 2007

DML

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Environmental degradation of the miticide cycloprate (hexadecyl cyclopropanecarboxylate). 4. Beagle dog metabolism

Cited by 28 publications

References 8 publications

Metabolism of S-1108, a new oral cephem antibiotic, and metabolic profiles of its metabolites in humans

Metabolism of S-1108, a new oral cephem antibiotic, and metabolic profiles of its metabolites in humans

Substrate specificity for carnitine and glycine conjugation of branched side-chain and cyclic side-chain carboxylic acids in various experimental animals

Disposition of Vorinostat, A Novel Histone Deacetylase Inhibitor and Anticancer Agent, in Preclinical Species

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