Studying cytochrome P450 kinetics in drug metabolism

被引：1

作者：

Kramer, Melissa A. ^{[1
]}

Tracy, Timothy S. ^{[1
]}

机构：

[1] Univ Minnesota, Coll Pharm, Dept Expt & Clin Pharmacol, Minneapolis, MN 55455 USA

来源：

EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY | 2008年 / 4卷 / 05期

关键词：

atypical; biphasic; cytochrome P450; hepatocytes; heterotropic activation kinetics; K-m; microsomes; sigmoidal; substrate inhibition; V-max;

D O I：

10.1517/17425255.4.5.591

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Background: Determination of cytochrome P450 enzyme-mediated kinetics in vitro can be useful for predicting drug dosing and clearance in humans. Expressed P450s, human liver microsomes, human hepatocytes (both fresh and cryopreserved), and human liver slices are used to estimate Km and V-max values for determination of intrinsic clearance of the drug for scale-up to predict in vivo clearance. Objective: To describe the advantages and disadvantages of the various in vitro systems used to estimate kinetic parameters for disposition of drugs and the various kinetic profiles that can be observed. Methods: A review of the literature was conducted to evaluate the utility of the various in vitro preparations, the methods for determining kinetic parameters and the types of kinetic profiles that may be observed. Results/conclusions: The choice of in vitro system for determining kinetic parameters will depend on the objective of the studies, as each system has advantages and disadvantages. Kinetic parameter determinations must be carefully assessed to assure that the correct kinetic model is applied and the most accurate kinetic parameters are determined.

引用

页码：591 / 603

页数：13

共 74 条

[1]

[Anonymous], 2003, MODERN PHARM CLIN AP

[2] NOVEL EXOGENOUS HEME-DEPENDENT EXPRESSION OF MAMMALIAN CYTOCHROME-P450 USING BACULOVIRUS [J].

ASSEFFA, A ;

SMITH, SJ ;

NAGATA, K ;

GILLETTE, J ;

GELBOIN, HV ;

GONZALEZ, FJ .

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1989, 274 (02) :481-490

[3] The influence of nonspecific microsomal binding on apparent intrinsic clearance, and its prediction from physicochemical properties [J].

Austin, RP ;

Barton, P ;

Cockroft, SL ;

Wenlock, MC ;

Riley, RJ .

DRUG METABOLISM AND DISPOSITION, 2002, 30 (12) :1497-1503

[4] Preservation of the synthetic and metabolic capacity of isolated human hepatocytes by coculture with human biliary epithelial cells [J].

Auth, MKH ;

Woitaschek, D ;

Beste, M ;

Schreiter, T ;

Kim, HS ;

Oppermann, E ;

Joplin, RE ;

Baumann, U ;

Hilgard, P ;

Nadalin, S ;

Markus, BH ;

Blaheta, RA .

LIVER TRANSPLANTATION, 2005, 11 (04) :410-419

[5] Time course of cytochromes P450 decline during rat hepatocyte isolation and culture: effect of L-NAME [J].

Binda, D ;

Lasserre-Bigot, D ;

Bonet, A ;

Thomassin, M ;

Come, MP ;

Guinchard, C ;

Bars, R ;

Jacqueson, A ;

Richert, L .

TOXICOLOGY IN VITRO, 2003, 17 (01) :59-67

[6] The conduct of in vitro and in vivo drug-drug interaction studies: A Pharmaceutical Research and Manufacturers of America (PhRMA) perspective [J].

Bjornsson, TD ;

Callaghan, JT ;

Einolf, HJ ;

Fischer, V ;

Gan, L ;

Grimm, S ;

Kao, J ;

King, SP ;

Miwa, G ;

Ni, L ;

Kumar, G ;

McLeod, J ;

Obach, RS ;

Roberts, S ;

Roe, A ;

Shah, A ;

Snikeris, F ;

Sullivan, JT ;

Tweedie, D ;

Vega, JM ;

Walsh, J ;

Wrighton, SA .

DRUG METABOLISM AND DISPOSITION, 2003, 31 (07) :815-832

[7] An update on in vitro test methods in human hepatic drug biotransformation research: pros and cons [J].

Brandon, EFA ;

Raap, CD ;

Meijerman, I ;

Beijnen, JH ;

Schellens, JHM .

TOXICOLOGY AND APPLIED PHARMACOLOGY, 2003, 189 (03) :233-246

[8]

Busby WF, 1999, DRUG METAB DISPOS, V27, P246

[9]

BUTERS JTM, 1994, DRUG METAB DISPOS, V22, P688

[10]

Carlile DJ, 1997, DRUG METAB DISPOS, V25, P903

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