The influence of bacterial gut hydrolysis on the fate of orally administered isonicotinuric acid in man

Boxenbaum, Harold; Jodhka, Gurcharan S.; Ferguson, Anne C.; Riegelman, Sidney; MacGregor, Thomas R.

doi:10.1007/bf01059763

Cited by 26 publications

(9 citation statements)

References 40 publications

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“…These second peaks are of the same order or larger than the primary peaks observed at about 3-5 h after dosage. Biphasic plasma elimination time curves are observed for other compounds [16,17] and it is observed in Table 1 of Amoah et al [18] that there is a suggestion of secondary peaks in 12 out of 16 plasma perhexiline or M1 elimination profiles. This phenomenon offers alternatives to extensive tissue binding as an explanation for the very slow elimination of a single dose of perhexiline in man.…”

Section: Discussionmentioning

confidence: 86%

“…stilboestrol and digitoxin [19], while elimination times may be shortened and plasma concentrations reduced if the enterohepatic recirculation is interrupted, e.g. by biliary diversion [17] or by interference with bacterial gut hydrolysis [16]. It is highly likely that slow elimination, which is so accentuated in the poor oxidizer, is responsible for the selective production of adverse effects such as hepatotoxicity [3] and peripheral neuropathy [2] in that phenotype.…”

Section: Discussionmentioning

confidence: 99%

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Studies on the metabolism of perhexiline in man

Cooper

Evans

Price

1987

Eur J Clin Pharmacol

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We have studied the disposition of perhexiline and its two major metabolites, M1 and M3, in healthy volunteers and in patients with biliary T-tube drains after cholecystectomy. In healthy volunteers the genetic control for impaired hepatic oxidation is identical for debrisoquine, sparteine, and perhexiline. Poor metabolizers demonstrate markedly reduced production and excretion of the major metabolite, M1. Their production of M3 is also reduced, but to a lesser degree than for M1, confirming substrate stereoselectivity by hepatic oxidases. Biphasic urinary elimination of M1 and M3 is seen in intact extensive oxidizers, whereas only the first phase is apparent in patients with biliary T-tube drainage. This suggests the possibility of enterohepatic recycling of these compounds, which may account for their prolonged elimination. More than 90% of an ingested dose of perhexiline maleate remains unaccounted for at 24 h after ingestion, even in extensive metabolizers. A careful, radiolabelled tissue-distribution study is warranted to elucidate the complicated metabolic fate of perhexiline.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Studies on the metabolism of perhexiline in man

Cooper

Evans

Price

1987

Eur J Clin Pharmacol

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“…Similarly, isonicotinuric acid is readily metabolized back to isonicotinic acid in humans. 191 The enzyme involved in the glycine conjugation is glycine acyltransferase. A complication is that the formation of salicyluric acid is saturable192 and inducible by salicylic acid.…”

Section: Carboxylic Acidsmentioning

confidence: 99%

Pharmacokinetics of reversible metabolic systems

Cheng

Jusko

1993

Biopharm & Drug Disp

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“…Amide bonds of various N ‐aromatic acyl‐amino acid conjugates are stable in the upper intestine and hydrolyzed when they are incubated with the cecal contents of mammals 15–17. If a hydrophilic amino acid conjugate of 5‐ASA is administered orally, transcellular absorption by way of lipid membrane permeation might be limited in the upper intestine, and a large fraction of the dose might be delivered to the colon in intact form.…”

Section: Introductionmentioning

confidence: 99%