Muindi J R, Young C W, Warrell R P
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021.
Leukemia. 1994 Nov;8(11):1807-12.
The clinical pharmacology of all-trans retinoic acid (RA) has distinct differences from that of its widely studied stereoisomer 13-cis retinoic acid (cRA). RA is much more rapidly cleared from plasma following oral administration; their respective half-lives are < 1 h and 13 h. There is extensive accumulation of the 4-oxo-cRA in plasma following repeated doses of cRA, while 4-oxo-RA is only a minor metabolite in plasma following RA administration. The extent of isomerization in vivo differs for the two retinoids. In contrast to cRA, where up to a 1:3 ratio of RA to cRA is observed in patient plasma following drug administration, cRA concentrations in excess of 10 ng/ml are rarely observed in plasma of patients receiving exogenous RA. RA administration produces autoinduction of its own oxidative catabolism; this effect does not occur with cRA. These pharmacokinetic differences have been observed in leukemia and solid tumor patients. Detailed analysis of the results of the population studied suggest that both constitutive and RA-induced hypercatabolism of RA occurs. Both of these hypercatabolic states can be modulated by concurrent administration of ketoconazole, an inhibitor of cytochrome P-450 and lipoxygenase-mediated oxidations.
全反式维甲酸（RA）的临床药理学与其广泛研究的立体异构体13-顺式维甲酸（cRA）有明显差异。口服给药后，RA从血浆中清除的速度要快得多；它们各自的半衰期分别小于1小时和13小时。重复给予cRA后，4-氧代-cRA在血浆中有广泛蓄积，而给予RA后，4-氧代-RA只是血浆中的一种次要代谢产物。两种维甲酸在体内的异构化程度不同。与cRA不同，给药后患者血浆中观察到RA与cRA的比例高达1:3，而在接受外源性RA的患者血浆中很少观察到cRA浓度超过10 ng/ml。给予RA会导致其自身氧化分解代谢的自诱导；cRA不会出现这种效应。在白血病和实体瘤患者中均观察到了这些药代动力学差异。对所研究人群结果的详细分析表明，RA的组成性和RA诱导的高分解代谢均会发生。这两种高分解代谢状态均可通过同时给予酮康唑（一种细胞色素P-450和脂氧合酶介导氧化的抑制剂）来调节。
