新型、高亲和力和选择性多巴胺D3受体拮抗剂SB-277011在大鼠、犬和猴体内的药代动力学：体外/体内相关性及醛氧化酶的作用

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.

作者信息

Austin N E, Baldwin S J, Cutler L, Deeks N, Kelly P J, Nash M, Shardlow C E, Stemp G, Thewlis K, Ayrton A, Jeffrey P

机构信息

Department of Drug metabolism and Pharmacokinetics, GlaxoSmithKline, Welwyn, Hertfordshire, UK.

出版信息

Xenobiotica. 2001 Aug-Sep;31(8-9):677-86. doi: 10.1080/00498250110056531.

DOI:10.1080/00498250110056531

PMID:11569533

Abstract

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.

摘要

使用选择性多巴胺D3受体拮抗剂SB - 277011在大鼠、犬、食蟹猴和人的肝脏微粒体及匀浆中进行了体外研究，以关联该化合物的代谢速率与在大鼠、犬和食蟹猴体内的药代动力学。2. 在NADPH存在的情况下，SB - 277011在大鼠、犬、食蟹猴和人的肝脏微粒体中相对稳定，所有物种的内在清除率（CLi）均<2 ml min⁻¹ g⁻¹肝脏。在全肝匀浆中，SB - 277011在大鼠和犬中的代谢速率（CLi<2 ml min⁻¹ g⁻¹肝脏）与在肝脏微粒体中的相似，但在食蟹猴和人中（CLi分别为9.9和45 ml min⁻¹ g⁻¹肝脏），内在清除率分别比肝脏微粒体中的高约6倍和35倍。3. 在不存在NADPH的情况下，SR - 277011在食蟹猴和人的肝脏匀浆中迅速清除（CLi分别为7.4和27 ml min⁻¹ g⁻¹肝脏），表明该化合物的一个重要代谢途径是通过不依赖NADPH的非微粒体氧化途径。该途径对异香草醛抑制敏感，提示负责的酶是醛氧化酶。4. 体内药代动力学表明，SB - 277011在大鼠中的血浆清除率较低（20 ml min⁻¹ kg⁻¹），在犬中中等（14 ml min⁻¹ kg⁻¹），在食蟹猴中较高（58 ml min⁻¹ kg⁻¹），这与体外研究结果一致，表明食蟹猴代谢该化合物的能力更强。SB - 277011在大鼠、犬和食蟹猴中的口服生物利用度分别为35%、43%和2%。鉴于该化合物在食蟹猴中的高清除率，低口服生物利用度可能是由于首过消除率高，特别是通过醛氧化酶，而不是吸收不良。5. SB - 277011在人肝脏匀浆中的高体外清除率以及醛氧化酶参与SB - 277011的代谢表明该化合物在人体内的生物利用度可能较低。