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On the metabolism of clofibride, a hypolipaemic drug

The absorption and metabolism of clofibride, a new hypolipaemic drug of p‐chlorophenoxyisobutyric type, were investigated in the CD rat, the beagle and the olive baboon monkey. Clofibride is rapidly and massively resorbed and hydrolysed into 4‐chlorophenoxyisobutyric acid (CPIB) and 4‐hydroxy‐N‐dimethylbutyramide (HMB). CPIB, in free and glucuroconjugated form, and its metabolite, 4‐chlorophenol, in the form of the glucuronate ether, are found in the serum of the rat. HMB is rapidly metabolized. The half‐life of CPIB, the main active metabolite, in the serum is about 12 h in the rat, 43 ± 9 h in the dog and 6 ± 1 h in the baboon. In the rat, peak hypocholesterolaemic activity occurs late—24 h after administration of the drug and 20 h after peak concentration of CPIB in the blood. The half‐life of 4‐chlorophenol glucuronate ether in the serum is about 4 h whereas that of HMB is about 3 h. In the rat, the elimination of clofibride takes place mainly via the urine since 70% of the dose administered is found in the form of free or conjugated CPIB, 10% in the form of HMB or one of its metabolites, in 48 h samples of urine. Over the same period, faecal elimination accounts for no more than 2% of the dose ingested. In addition, in this species, the CPIB, 30% of which is secreted via the biliary route without being eliminated in the faeces, undergoes an enterohepatic circulation.