Subject Area物理化学
A simple sampling strategy with deoxyschizandrin to assess activities of CYP3A in vivo
Wu JJ(吴敬敬); Zhang YY(张延延); Hu Y(胡莹); Liang SC(梁思成); Yang L(杨凌)
Conference Name9th International Society for the Study of Xenobiotics
Conference Date2010-9-4
Conference Place土耳其
Funding Organization伊斯坦布尔
AbstractThe common method used for the determination of phenotyping of drug-metabolizing enzymes in vivo is using the parent compound depletion curve method to obtain the total clearance (CLt) under first-order (linear) conditions. CLt indirectly reflected the intrinsic clearance (CLint), a parameter representing the metabolic enzymes (or/and transporters) activity. However, such total clearance is the surrogate of the catalytic activity of a certain enzyme (CLint,met) only under these limitations: ① hepatic metabolism is the primary clearance pathway; ② hepatic clearance (CLh) is enzyme-capacity limited rather than blood-flow limited; ③ hepatic uptake is not a rate-limiting step in the elimination. An alternative approach was suggested where the CLint is substituted for the approximate maximal initial formation rate (Vmax, app) of a specific reaction metabolite in vivo, which can accurately reflect the specific enzyme activity and exclude other enzyme and non-metabolism factors. In contrast to the traditional method, this novel method is in need of saturated substrate concentration (≥ 5 Km generally) to acheive zero-order (non-linear) conditions. Our previous data have demonstrated the deoxyschizandrin (DS) was selectively metabolized to schizandrin (SZ) by CYP3A in human and rat. Applying the Vmax, app determination method, zero-order SZ formation kinetic period of 10~60 min in perfusate can be found at saturated substrate concentrations (40~85 μM) with recirculating perfused rat livers. In addition, albumin added to the perfusate did not affect the Vmax, app, in situ. In vivo results indicated that linear formation of SZ in plasma can be measured up to 15~25 min after intravenous administration of DS (5, 10, 25 mg/kg). Excellent correlation was observed among Vmax, in vitro (54.89±4.24 nM/min) with rat liver microsomes, Vmax, app, in situ (63.4±6.78 nM/min) with perfused rat livers and Vmax, app, in vivo (63.48±6.58 nM/min) with rat. We speculated that at least two blood samples would be needed to determine the Vmax, app in vivo. In conclusion, a simple sampling strategy using DS as a probe was developed to assess activity of CYP3A in vivo.
Document Type会议论文
Corresponding AuthorYang L(杨凌)
Recommended Citation
GB/T 7714
Wu JJ,Zhang YY,Hu Y,et al. A simple sampling strategy with deoxyschizandrin to assess activities of CYP3A in vivo[C],2010:78/2.
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