title: 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.
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.
authors.affiliation: Department of Drug metabolism and Pharmacokinetics, GlaxoSmithKline, Welwyn, Hertfordshire, UK. nigel_e_austin@gsk.com
authors.forename: N E
authors.initials: NE
authors.lastname: Austin
authors.forename: S J
authors.initials: SJ
authors.lastname: Baldwin
authors.forename: L
authors.initials: L
authors.lastname: Cutler
authors.forename: N
authors.initials: N
authors.lastname: Deeks
authors.forename: P J
authors.initials: PJ
authors.lastname: Kelly
authors.forename: M
authors.initials: M
authors.lastname: Nash
authors.forename: C E
authors.initials: CE
authors.lastname: Shardlow
authors.forename: G
authors.initials: G
authors.lastname: Stemp
authors.forename: K
authors.initials: K
authors.lastname: Thewlis
authors.forename: A
authors.initials: A
authors.lastname: Ayrton
authors.forename: P
authors.initials: P
authors.lastname: Jeffrey
mesh_terms: D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D018492:Dopamine Antagonists / Q000378:metabolism / Q000493:pharmacokinetics*; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009570:Nitriles / Q000378:metabolism / Q000493:pharmacokinetics*; D011804:Quinolines / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D050637:Receptors, Dopamine D3; D013045:Species Specificity; D044005:Tetrahydroisoquinolines
chemical_list: C493593:DRD3 protein, human; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493595:Drd3 protein, rat; D009570:Nitriles; D011804:Quinolines; D050637:Receptors, Dopamine D3; C409982:SB 277011; D044005:Tetrahydroisoquinolines; D009249:NADP; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase