Benoxaprofen - Toxicitiy


After the suspension of sales in 1982 the toxic effects which benoxaprofen might have on humans were looked into more deeply. The fairly planar compound of benoxaprofen seems to be hepa- and phototoxic in the human body.

Benoxaprofen has a rather long half life in man (t1/2= 20-30 h), undergoes biliary excretion and enterohepatic circulation and is also known to have a slow plasma clearance (CL p=4.5 ml/min). The half life may be further increased in elderly patients (>80 years of age) and in patients which already have an renal impairment increasing to figures as high as 148 hours.

The fetal hepatotoxicity of benoxaprofen can be attributed to the accumulation of the drug after a repeated dosage and also associated with the slow plasma clearance. The hepatic accumulation of the drug is presumably the cause for an increase in the activity of the hepatic cytochrome P450I which will oxygenate benaxoprofen and produce reactive intermediates. Benoxaprofen is very likely a substrate and weak inducer of cytochrome P450I and its enzyme family. Normally it is not metabolized by oxidative reactions but with the S(+) enantiomer of benoxaprofen and cytochrome P450I as a catalyst the oxygenation of the 4-chlorophenyl ring and of the aromatic ring of 2-phenyl propionic acid seems to be possible. Therefore the induction of a minor metabolic pathway leads to the formation of toxic metabolites in considerable amounts. The toxic metabolites may bind to vital intracellular macromolecules and may generate reactive oxygens by redox cycling if quinone is formed. This could also lead to a depletion of protective glutathione which is responsible for the detoxification of reactive oxygens.

The observed skin phototoxicity of patients treated with benoxaprofen can be explained with a look at the structure of the compound. There are significant structural similarities between the benzoxazole ring of benoxaprofen and the benzafuran ring of psoralen, a compound known to be phototoxic. The free decarboxylated derivate of the drug can produce singlet oxygen and superoxy anions in the presence of oxygen. Furthermore possible explanations for the photochemical decarboxylation and oxygen radical formation may be the accumulation of repeated dosage, the induction of cytochrome P450I and the emergence of reactive intermediates with covalent binding. The photochemical character of the compound can cause inflammation and severe tissue damage.

In animals peroxisomal proliferation is also observed but does not seem to be significant in man.

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