Disposition in rats and dogs of ciglitazone, a new antidiabetic agent.

Abstract

Oral 14C-ciglitazone was well absorbed by rats to give a maximum plasma level at two hours and an apparent half-life of 4.9 h. In dogs, the plasma level of the compound, after oral administration, reached a plateau at one hour, persisted till ten hours and then declined with a half-life of 23.5 h. In rats, plasma levels of metabolites were higher than those of unchanged ciglitazone, whereas the reverse was noted in dogs. Plasma metabolites were the monohydroxycyclohexyl derivatives (mono-ol) and monoketocyclohexyl derivatives (mono-oxo), together with other components consisting largely of dihydroxycyclohexyl derivatives (di-ol) and unknown polar metabolites. Metabolites found in rats were pharmacologically active trans-4'-ol, 3'-ol, 4'-oxo, cis-4'-ol, 3'-oxo and 2'-ol in the decreasing order listed, and those in dogs were 3'- and/or 4'-ols. Ciglitazone was highly bound to plasma protein of both animals. After oral administration of 14C-ciglitazone to rats, 14C was widely distributed in tissues, with the highest concn. in the gastrointestinal tract, followed by liver, adipose, plasma, adrenal gland, kidney, pancreas, spinal cord, heart and lung, and the lowest in the brain. The concn. of 14C in erythrocytes of rats and dogs was very low, as was the level of 14C in rat fetuses. Elimination of 14C-ciglitazone was complete within 96 h in rats and 144 h in dogs. In both animals, the dosed 14C was excreted largely in faeces as metabolites, with the remainder appearing in urine. Biliary excretion and reabsorption of 14C were obvious in rats. In both rats and dogs, the major metabolites found in faeces were 3'- and/or 4'-ols and other components derived from bile, and those in urine were other components. On repeated oral administration of 14C-ciglitazone to rats for seven days, no accumulation of 14C occurred in plasma and tissues, and 97.5% of the dose was eliminated from the body within 96 h after the last administration.