Pharmacokinetics of the novel, high-affinity and selective dopamine D3 receptor antagonist SB-277011 in rat, dog and monkey: in vitro/in vivo correlation and the role of aldehyde oxidase

1. In vitro studies with the selective dopamine D3 receptor antagonist SB-2 77011 were conducted in liver microsomes and homogenates from rat, dog, cyn omolgus monkey and human to correlate the rate of metabolism with the in vi vo pharmacokinetics of the compound in rat, dog and cynomolgus monkey. 2. In the presence of NADPH, SB-277011 was relatively stable in the presenc e of liver microsomes from rat, dog, cynomolgus monkey and human with an in trinsic clearance (CLi) of <2 ml min(-1) g(-1) liver for all species. In to tal liver homogenates, SB-277011 was metabolized at a similar rate in rat a nd dog (CLi < 2 ml min(-1) g(-1) liver) to that in liver microsomes but in cynomolgus monkey and human (CLi=9.9 and 45 ml min(-1) g(-1) liver, respect ively) the intrinsic clearance was similar to6- and 35- fold higher, respec tively, than that in liver microsomes. 3. In the absence of NADPH, SB-277011 was rapidly cleared in liver homogena tes from cynomolgus monkey and human (CLi=7.4 and 27 ml min(-1) g(-1) liver , respectively) demonstrating that a significant pathway of metabolism of t his compound was via an NADPH-independent non-microsomal oxidative route. T his pathway was sensitive to inhibition with isovanillin suggesting that th e enzyme responsible was aldehyde oxidase. 4. The in vivo pharmacokinetics showed that the plasma clearance of SB-2770 11 was low in rat (20 ml min(-1) kg(-1)), moderate in dog (14 ml min(-1) kg (-1)) and high in cynomolgus monkey (58 ml min(-1) kg(-1)), which is consis tent with the in vitro findings and demonstrated a greater capacity for the monkey to metabolize this compound. The oral bioavailability of SB-277011 in rat, dog and cynomolgus monkey was 35, 43 and 2%, respectively. Given th e high clearance of this compound in cynomolgus monkey, the low oral bioava ilability is probably as a result of high first-pass elimination, specifica lly by aldehyde oxidase, rather than poor absorption. 5. The high in vitro clearance of SB-277011 in human liver homogenates and the involvement of aldehyde oxidase in the metabolism of SB-277011 indicate s that the bioavailability of the compound is likely to be low in human.