Disposition and Metabolism of Benoxaprofen in Laboratory Animals and Man

Abstract

1. The absorption, distribution, metabolism and excretion of benoxaprofen, a novel anti-inflammatory compound, has been studied in the dog, mouse, rat, rabbit, rhesus monkey and man. 2. Benoxaprofen was well absorbed after oral administration of doses of 1 to 10 mg/kg in all six species. Only unchanged drug was detected in plasma. It was extensively bound to plasma proteins, the highest binding occurring in man (99.8%) and rhesus monkey (99.6%). 3. Species differences were observed in the plasma elimination half-life, the longest being in man (33 h). The rat and mouse also had high values (28 and 24 h respectively) whereas in the other species, values were less than 13 h. 4. After an oral dose of [14C]benoxaprofen (20 mg/kg) to female rats, tissue concn. was highest in liver, kidney, lungs, adrenals and ovaries. Tissue distribution in the pregnant rat was identical to the normal female. The compound was found in the foetus but at a concn. lower than in all maternal organs. 5. There was a marked species difference in the route of excretion. In man, rhesus monkey and rabbit, excretion in the urine was a major route, whilst biliary--faecal excretion was the only effective route in the rat and dog. 6. No major metabolic transformation of benoxaprofen was observed. Man and dog excreted the compound predominantly as the ester glucuronide whereas the rat, mouse, rabbit and rhesus monkey excreted a large proportion of the dose unchanged.

The metabolic chiral inversion of 2-arylpropionic acids—a novel route with pharmacological consequences

“…In common laboratory species marked differences are observed in the route of excretion. both the drug and unidentified polar metabolites being detected in both urine and faeces (Chatfield & Green 1978). The stereoselective inversion of the R( -)-enantiomer to the S( +)-enantiomer was demonstrated by Bopp et al (1979) using a g.1.c.…”

“…(R,compound VIII;Fig. 3) Benoxaprofen is metabolized in man to yield the acyl glucuronide, both free acid and glucuronide being excreted in urine (Chatfield & Green 1978). In common laboratory species marked differences are observed in the route of excretion.…”

Pharmacokinetic studies with benoxaprofen in man: prediction of steady‐ state levels from single‐dose data.

“…The long half-life must be due, at least in part, to the lack of metabolic degradation of this compound and its extensive (99.8%) binding to human plasma proteins (Chatfield & Green, 1977). This high plasma-protein binding is probably also responsible for the small volumes of distribution, the two compartments totalling only 140 ml/kg body weight.…”

“…After intravenous administration of benoxaprofen to animals the decline in plasma level of the compound followed a biphasic pattern (Chatfield & Green, 1977 Gibaldi, Nagashima & Levy (1969).…”

Glycerolysis of Acyl Glucuronides as an Artifact of in Vitro Drug Metabolism Incubations

“…The metabolism of benoxaprofen to its acyl glucuronide was demonstrated to be the quantitatively most important metabolic pathway in the human and animal species (Chatfield and Green, 1978), and benoxaprofen acyl glucuronide has been implicated as the entity responsible for toxicity. Covalent bonding of benoxaprofen acyl glucuronide has been demonstrated in vitro and in vivo, with albumin as a prevalent target (Dahms and Spahn-Langguth, 1996;Dong et al, 2005).…”