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

Abstract

1. In vitro studies with the selective dopamine D3 receptor antagonist SB-277011 were conducted in liver microsomes and homogenates from rat, dog, cynomolgus monkey and human to correlate the rate of metabolism with the in vivo pharmacokinetics of the compound in rat, dog and cynomolgus monkey. 2. In the presence of NADPH, SB-277011 was relatively stable in the presence of liver microsomes from rat, dog, cynomolgus monkey and human with an intrinsic clearance (CLi) of < 2 ml min(-1) g(-1) liver for all species. In total liver homogenates, SB-277011 was metabolized at a similar rate in rat and 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, respectively) the intrinsic clearance was approximately 6- and 35-fold higher, respectively, than that in liver microsomes. 3. In the absence of NADPH, SR-277011 was rapidly cleared in liver homogenates 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 this compound was via an NADPH-independent non-microsomal oxidative route. This pathway was sensitive to inhibition with isovanillin suggesting that the enzyme responsible was aldehyde oxidase. 4. The in vivo pharmacokinetics showed that the plasma clearance of SB-277011 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 consistent 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 the high clearance of this compound in cynomolgus monkey, the low oral bioavailability is probably as a result of high first-pass elimination, specifically 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 indicates that the bioavailability of the compound is likely to be low in human.

Blockade of mesolimbic dopamine D3 receptors inhibits stress-induced reinstatement of cocaine-seeking in rats

“…1). SB-277011A (3, 6, and 12 mg/kg, IP) was given 60 min before reinstatement testing, as its peak drug level in rat brain is achieved approximately 60 min after systemic administration (Austin et al 2001). In the intracranial microinjection experiments, reinstatement testing began after 30 min, based on pilot studies showing maximal SB-277011A effects 30 min after being locally administered into NAcc.…”

The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence

“…SB-277011-A has also been shown to readily penetrate the rat brain with a steady-state brain/ plasma ratio of 3.6:1 [229,283]. In the rat, SB-277011-A has an oral bioavailability of 43%, shows low clearance, and a half-life of 2.0 h. The drug appears to be metabolized by the liver enzyme hepatic aldehyde oxidase [16].…”

Selective Antagonism at Dopamine D3 Receptors Enhances Monoaminergic and Cholinergic Neurotransmission in the Rat Anterior Cingulate Cortex

“…The dose of SB-277011-A has been chosen based on pharmacokinetic characteristics (Reavill et al, 2000;Austin et al, 2001) and behavioral properties reported in previous studies (Reavill et al, 2000;Di Ciano et al, 2001;Le Foll et al, 2002;Vorel et al, 2002). Doses of clozapine, olanzapine, haloperidol, and sulpiride were based on previous behavioral and in vivo neurochemical studies (Parada et al, 1997;Li et al, 1998;Kuroki et al, 1999;Heidbreder et al, 2001a;Ichikawa et al, 2002).…”