Pharmacokinetics of ochratoxin A and its metabolites in rats.
Ochratoxin A (OA) is a mycotoxin that is produced on moist grain. It is commonly found in the blood of swine in western Canada and is a potent nephrotoxic, carcinogen, and immunosuppressive agent. The pharmacokinetic characteristics of six analogs of OA including OA, OB (OA without chloride), OC (OA ethyl ester), and some metabolites, such as O alpha (OA without phenylalanine), OA-OH (hydroxylated OA), and a newly discovered form of OA, OP-OA (lactone opened ring of OA), were investigated in rats after a single intravenous administration of the compounds. All of the ochratoxin analogs were distributed following a two compartment open model. The elimination half-lives of OA, OP-OA, O alpha, OA-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 were 3.1, 3.6, 40, 65, and 43 ml/hr kg, respectively. OA, OB, and O alpha were mainly cleared in the urine (> or = 48%), OA-OH in the bile (41%), and OP-OA as metabolites (43%). Metabolism accounted 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. Procedures should be devised to enhance the conversion in the body of OA to O alpha, OA-OH, or other metabolites as this would shorten its half-life and therefore its toxicity.
Li
S
S
Department of Animal Science, University of Manitoba, Winnipeg, Canada.
Marquardt
R R
RR
Frohlich
A A
AA
Vitti
T G
TG
Crow
G
G
D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002273:Carcinogens / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D007275:Injections, Intravenous; D009183:Mycotoxins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D009793:Ochratoxins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014140:Tracheotomy
D002273:Carcinogens; D009183:Mycotoxins; D009793:Ochratoxins; C025589:ochratoxin A