Pang K S
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Drug Metab Dispos. 1995 Feb;23(2):166-77.
Interpretation of rate constants in the sequential metabolism of two different primary metabolites (MIA and MIB) for formation of a common, secondary metabolite (MII) after drug administration requires theoretical development of formulations that govern mass transfer during intravenous and oral administrations. Two cases (a and b) were presently considered for metabolism occurring only in the first-pass organs (intestine and liver) for flow-limited drugs and primary and secondary metabolites: (case a) wherein drug formed only the two primary metabolites, with the fractions of total body clearance that formed MIA and MIB, being denoted by f1 and f2, respectively, and (case b) wherein other additional elimination pathways for drug were present. MIA and MIB only partially formed MII (denoted by fMIA and fMIB, respectively), because provision was made for alternate elimination pathways; the fractional clearance in the formation of MII from MIA and MIB were fMIA and fMIB, respectively. Drug was metabolized to MIA than MII within the gut lumen with oral drug administration; the MIA and MII formed were further absorbed. Triangular matrices were found to result from mass transfer equations for first-order conditions with oral and intravenous administrations. Upon inversion of the matrices, the areas under the curve for drug and metabolite species were obtained after multiplication by the administered dose and division by the volume of the species considered. However, the dose-corrected area under the curve was used as the basis for comparison. Case-independent solutions were obtained for the fractions absorbed (Fa, FaMIA, FaMIB) and the availabilities (F, F(MIA), F(MIB)) of drug and the primary metabolites, and for f1, f2, f1/f2, fMIA/fMIB, and (f1fMIA)/(f2fMIB) (ratio of effective clearances of MII formation from D via MIA and MIB). Case-dependent solutions also existed. For case a (f1 + f2 = 1), the fraction of total body clearance that formed MIA (f1) or MIB (f2) was solved with the area under the curve of MII after intravenous D, MIA, and MIB administrations. For case b, however, the same constants were obtained after greater manipulation, and entailed oral administration of the metabolites. Although solutions for the ratios of f1/f2 and (f1fMIA)/(f2fMIB) were found, the fractional clearances in formation of MII from MIA (fMIA) and MIB (fMIB) were, however, not provided in both cases unless MII was completely absorbed.
药物给药后，两种不同的初级代谢产物（MIA和MIB）依次代谢形成一种共同的次级代谢产物（MII），对速率常数的解释需要建立理论公式，以控制静脉内和口服给药期间的质量传递。目前考虑了两种情况（a和b），适用于仅在首过器官（肠道和肝脏）中发生代谢的血流受限药物以及初级和次级代谢产物：（情况a）药物仅形成两种初级代谢产物，形成MIA和MIB的全身清除率分数分别用f1和f2表示；（情况b）药物存在其他额外的消除途径。MIA和MIB仅部分形成MII（分别用fMIA和fMIB表示），因为考虑了替代消除途径；从MIA和MIB形成MII的清除率分数分别为fMIA和fMIB。口服给药时，药物在肠腔内代谢为MIA而非MII；形成的MIA和MII会进一步被吸收。对于口服和静脉给药的一级条件，质量传递方程可得到三角矩阵。矩阵求逆后，将给药剂量乘以并除以所考虑物种的体积，可得到药物和代谢产物物种的曲线下面积。然而，以剂量校正后的曲线下面积作为比较的基础。获得了药物及初级代谢产物的吸收分数（Fa、FaMIA、FaMIB）和可用性（F、F(MIA)、F(MIB)），以及f1、f2、f1/f2、fMIA/fMIB和(f1fMIA)/(f2fMIB)（从D经由MIA和MIB形成MII的有效清除率之比）的与情况无关的解。也存在与情况相关的解。对于情况a（f1 + f2 = 1），通过静脉注射D、MIA和MIB后MII的曲线下面积求解形成MIA（f1）或MIB（f2）的全身清除率分数。然而，对于情况b，经过更多操作后得到相同的常数，这需要口服代谢产物。尽管找到了f1/f2和(f1fMIA)/(f2fMIB)的比值解，但在两种情况下，除非MII被完全吸收，否则均未提供从MIA（fMIA）和MIB（fMIB）形成MII的清除率分数。
