Disposition of the antipsychotic agent CI-1007 in rats, monkeys, dogs, and human cytochrome P450 2D6 extensive metabolizers. Species comparison and allometric scaling.
The disposition of CI-1007 (I), an antipsychotic dopamine agonist, was studied after iv or po administration to rats, monkeys, and dogs and po administration to human cytochrome P450 2D6 extensive metabolizers (EMs). I was extensively metabolized after po administration, with high hepatic clearance (CL) values and negligible urinary excretion. Values for systemic plasma CL (28-40 ml/min/kg) suggested hepatic plasma flow-limited CL. The oral CL of I was similar among the species. Strong correlation was achieved in interspecies scaling for CL. After oral administration of [14C]I, the major route of 14C elimination in rats was in the bile (64%), followed by feces (29%) and urine (3.2%). Fecal excretion (64%) was the major route of 14C elimination in monkeys, followed by urine (14%). Three hydroxy metabolites, i.e. PD 147693 (II), PD 149394 (III), and PD 155144 (IV), and two sulfates, i.e. PD 163637 (VI) and PD 163639 (VIII), were identified in monkey plasma, urine, or feces. VIII was the major metabolite excreted in monkey urine, and VI was the major component in feces. Trace amounts of II, VI, and VIII were detected in the plasma and urine of human EMs but not in rats or dogs. II is an active metabolite that was present in all species. After oral administration, observed maximal plasma concentration and AUC values for II were higher than the corresponding values for I in dog plasma, approximately 20-40% of the values for I in monkeys and human EMs, and <5% of the values for I in rat plasma. Although the metabolic profiles differ among species, strong correlation was achieved in allometric scaling because the elimination of I from the body is mainly limited by hepatic blood flow.