Pharmacokinetics of ochratoxin A in animals.
The fate of ochratoxin A has been studied in laboratory rodents and in breeding animals. In rats, orally administered ochratoxin A is readily absorbed, and considerable amounts of the toxin are detected in plasma, where maximal concentrations occur 2-4 h after administration. Pharmacokinetic analysis of curves of plasma level versus time suggests its distribution in two distinct body compartments. The half-time of the toxin depends on both the dose and the animal species, varying from 0.7 h in fish to 840 h in monkeys. In plasma, the toxin is bound to albumin, like many acidic compounds. This interaction is competitively inhibited by phenylbutazone, ethylbiscoumacetate and sulfamethoxy-pyridazine and is decreased in albumin-deficient rats. The hydrolysis of ochratoxin A to an isocoumarin derivative (ochratoxin alpha) is the major metabolic pathway. This detoxication is brought about by animal and bacterial carboxypeptidases and takes place in the rumen and large intestine. 4-Hydroxyochratoxin A is the main hepatic metabolite, and its formation appears to be polymorphic, like debrisoquine 4-hydroxylation. The ratio of 4-hydroxyochratoxin A to ochratoxin A excreted in urine may be linked to the carcinogenic potential of the toxin, as the metabolite is almost as effective an immunosuppressor as ochratoxin A. After undergoing enterohepatic circulation, the toxin and ochratoxin alpha are excreted in faeces and urine as various unidentified metabolites. Transport of the mycotoxin in the kidney is mediated by the renal organic anion transport system, and renal metabolism may contribute to detoxification. Although dose-dependent placental transfer of ochratoxin A has been described in rodents, the toxin does not cross the placenta into fetuses of sows administered a low dose (0.38 mg/kg) orally. Its diffusion into the milk of female rabbits is seen after intravenous administration, but in cows given 50 mg of the mycotoxin, barely detectable amounts of ochratoxin alpha were recovered in milk. Ochratoxin A is preferentially distributed in liver, kidney, muscle and fat. The experimental data are in close accordance with several reports on the spontaneous occurrence of unchanged toxin residues in blood and kidneys of slaughter pigs.
Galtier
P
P
Laboratoire de Pharmacologie-Toxicologie, Institut National de la Recherche Agronomique, Toulouse, France.
D000418:Albumins / Q000378:metabolism; D000818:Animals; D000829:Animals, Domestic / Q000378:metabolism; D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004531:Eggs / Q000032:analysis; D005260:Female; D005399:Fishes / Q000378:metabolism; D000882:Haplorhini / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D007408:Intestinal Absorption; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008431:Maternal-Fetal Exchange; D008892:Milk / Q000032:analysis; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009793:Ochratoxins / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D011200:Poultry / Q000378:metabolism; D011247:Pregnancy; D011485:Protein Binding; D051381:Rats; D012377:Rodentia / Q000378:metabolism; D013552:Swine / Q000378:metabolism; D014018:Tissue Distribution
D000418:Albumins; D009793:Ochratoxins; C000426:5-chloro-8-hydroxy-3,4-dihydro-3-methylisocoumarin-7-carboxylic acid; C025589:ochratoxin A; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; C025650:4-hydroxyochratoxin A