PHARMACOKINETICS OF OCHRATOXIN-A AND ITS METABOLITES IN RATS

Ochratoxin A (OA) is a mycotoxin that is produced on moist grain. It i s commonly found in the blood of swine in western Canada and is a pote nt nephrotoxic, carcinogen, and immunosuppressive agent. The pharmacok inetic characteristics of six analogs of OA including OA, OB (OA witho ut chloride), OC (OA ethyl ester), and some metabolites, such as O alp ha (OA without phenylalanine), OA-OH (hydroxylated GA), and a newly di scovered form of OA, OP-OA (lactone opened ring of GA), were investiga ted in rats after a single intravenous administration of the compounds . All of the ochratoxin analogs were distributed following a two compa rtment open model. The elimination half-lives of OA, OP-OA, O alpha, O A-OH, OB, and OC were 103+/-16, 50.5+/-2.8, 9.6+/-2.3, 6+/-0.9, 4.2+/- 1.2, and 0.6+/-0.2 hr, respectively. Total body clearance of OA, OP-OA , O alpha, OA-OH, and OB via the bile, urine, and metabolic routes wer e 3.1, 3.6, 40, 65, and 43 ml/hr kg, respectively. OA, OB, and O alpha were mainly cleared in the urine (greater than or equal to 48%), OA-O H in the bile (41%), and OP-OA as metabolites (43%). Metabolism accoun ted for 43, 44, 33, and 29% of the total clearance of OA, O alpha, OA- OH, and OB, respectively. It is concluded that OA has a long half-life and is very slowly cleared from the body and that its metabolites are cleared at a much faster rate with much shorter half-lives. Procedure s should be devised to enhance the conversion in the body of OA to O a lpha, OA-OH, or other metabolites as this would shorten its half-life and therefore its toxicity. (C) 1997 Academic Press.