Abstract
The anti-allergy drug FPL 52757 (Fisons Ltd. ,) 6,8-diethyl-5-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid produced mild and reversible hepatotoxicity in some patients during clinical trials. The purpose of this work was to elucidate the mechanism by which FPL 52757 caused hepato-toxicity. However, since further humans could not be tested the work is limited to animal models. Toxicity studies showed that the beagle dog was the only animal species of ten tested which was readily susceptible to the hepatotoxic effect of the compound. In this project hepatotoxicity could not be demonstrated in ferrets or rats in special studies designed to reduce resistance to drug-induced hepatotoxicity. Similarly, hepatic microsomal enzyme induction in dogs by pretreatment with phenobarbitone and protection against cytotoxicity by pretreatment with methionine provided no evidence for involvement of a reactive metabolite in the hepatoxicity. Work by Fisons and additional studies in this project showed that the compound was extensively metabolised and rapidly eliminated by most species. Plasma clearance by the dog and man was in comparison slow,and due mainly to elimination of unchanged compound. As the dog and man are particularly susceptible to FPL 52757 induced hepatotoxicity the parent compound was implicated as the hepatotoxic agent. Species which cleared the compound rapidly compared with the dog did not readily show a hepatotoxic response. The toxicity of FPL 52757 in retrograde biliary infusion studies in rat and in the lysis of erythrocytes was studied and related to the detergent properties of the drug. Other chromones were also examined and a detergency/toxicity/structure/activity relationship was established. Pharmacokinetic studies in dog were carried out and showed that FPL 52757 resulted in increases in biliary excretion of alkaline phosphatase, gamma glutamyl-transpeptidase and 5'-nucleotidase which parallelled the biliary concentration of FPL 52757 and was accompanied by reduction in bile flow. The excretory mechanism of FPL 52757 in the biliary tract was shown to be saturable and could result in high hepatocellular drug concentration and subsequent liver damage in the dog. By implication from this work the mild hepatotoxic effect in man was likely to have been caused by the slow clearance and consequent build up in the liver and biliary tract of unchanged FPL 52757, the toxicity observed being mediated by the membrane damaging potential of high concentrations of the compound. As a consequence of this work it could confidently be predicted that lower concentrations would be perfectly safe in man.