On the metabolism of clofibride, a hypolipaemic drug

Abstract

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.