Predictions of cytochrome P450-mediated drug-drug interactions using cryopreserved human hepatocytes: Comparison of plasma and protein-free media incubation conditions

Drug Metabolism and Disposition

Volumn 40, Issue 4, 2012, Pages 706-716

  Mao, Jialin ^a,c   Mohutsky, Michael A ^a   Harrelson, John P ^b   Wrighton, Steven A ^a   Hall, Stephen D ^a  

^a ELI LILLY AND COMPANY   (United States)

^b PACIFIC UNIVERSITY   (United States)

^c GENENTECH INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA HYDROXYMIDAZOLAM; APREPITANT; BUFURALOL; CONIVAPTAN; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 3A; DESIPRAMINE; DICLOFENAC; DIPHENHYDRAMINE; DULOXETINE; ENCAINIDE; FLUCONAZOLE; FLUINDOSTATIN; GLIMEPIRIDE; IBUPROFEN; KETOCONAZOLE; LOSARTAN; METOPROLOL; MICONAZOLE; MIDAZOLAM; NEFAZODONE; PAROXETINE; PHENYTOIN; QUINIDINE; SERTRALINE; SULFAPHENAZOLE; TOLBUTAMIDE; UNINDEXED DRUG; VORICONAZOLE;

AREA UNDER THE CURVE; ARTICLE; CATALYSIS; CELL LEVEL; CELL VIABILITY; COMPARATIVE STUDY; CONCENTRATION RESPONSE; CONTROLLED STUDY; CRYOPRESERVATION; DRUG ANTAGONISM; DRUG BLOOD LEVEL; DRUG DEGRADATION; DRUG DISPOSITION; DRUG METABOLISM; DRUG POTENCY; DRUG POTENTIATION; DRUG SOLUBILITY; DRUG STRUCTURE; ENZYME ACTIVITY; ENZYME INHIBITION; HUMAN; HUMAN CELL; HYDROXYLATION; IC 50; LIQUID CHROMATOGRAPHY; LIVER CELL; MATHEMATICAL ANALYSIS; MATHEMATICAL MODEL; MICHAELIS MENTEN KINETICS; PLASMA; PREDICTION; PRIORITY JOURNAL; TANDEM MASS SPECTROMETRY;

ARYL HYDROCARBON HYDROXYLASES; CELL CULTURE TECHNIQUES; CELLS, CULTURED; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; CRYOPRESERVATION; CULTURE MEDIA; CULTURE MEDIA, SERUM-FREE; CYTOCHROME P-450 CYP2D6; CYTOCHROME P-450 CYP3A; CYTOCHROME P-450 ENZYME SYSTEM; DICLOFENAC; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG INTERACTIONS; ENZYME INHIBITORS; ETHANOLAMINES; HEPATOCYTES; HUMANS; HYDROXYLATION; MIDAZOLAM; PLASMA; PREDICTIVE VALUE OF TESTS; SUBSTRATE SPECIFICITY; TANDEM MASS SPECTROMETRY;

EID: 84858414753     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.111.043158     Document Type: Article

References (84)

1. Albers LJ, Reist C, Helmeste D, Vu R, and Tang SW (1996) Paroxetine shifts imipramine metabolism. Psychiatry Res 59:189-196. (Pubitemid 26058112)
2. Alderman J, Preskorn SH, Greenblatt DJ, Harrison W, Penenberg D, Allison J, and Chung M (1997) Desipramine pharmacokinetics when coadministered with paroxetine or sertraline in extensive metabolizers. J Clin Psychopharmacol 17:284-291. (Pubitemid 27312427)
3. Andersson TB, Bredberg E, Ericsson H, and Sjöberg H (2004) An evaluation of the in vitro metabolism data for predicting the clearance and drug-drug interaction potential of CYP2C9 substrates. Drug Metab Dispos 32:715-721. (Pubitemid 38821872)
4. Ayesh R, Dawling S, Hayler A, Oates NS, Cholerton S, Widdop B, Idle JR, and Smith RL (1991) Comparative effects of the diastereoisomers, quinine and quinidine in producing phenocopy debrisoquine poor metabolisers (PMs) in healthy volunteers. Chirality 3:14-18.
5. Back DJ, Tjia J, Mönig H, Ohnhaus EE, and Park BK (1988) Selective inhibition of drug oxidation after simultaneous administration of two probe drugs, antipyrine and tolbutamide. Eur J Clin Pharmacol 34:157-163. (Pubitemid 18091931)
6. Bergstrom RF, Peyton AL, and Lemberger L (1992) Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther 51:239-248.
7. Black DJ, Kunze KL, Wienkers LC, Gidal BE, Seaton TL, McDonnell ND, Evans JS, Bauwens JE, and Trager WF (1996) Warfarin-fluconazole. II. A metabolically based drug interaction: in vivo studies. Drug Metab Dispos 24:422-428.
8. Blanchard N, Hewitt NJ, Silber P, Jones H, Coassolo P, and Lavé T (2006) Prediction of hepatic clearance using cryopreserved human hepatocytes: a comparison of serum and serum-free incubations. J Pharm Pharmacol 58:633-641.
9. Blum RA, Wilton JH, Hilligoss DM, Gardner MJ, Henry EB, Harrison NJ, and Schentag JJ (1991) Effect of fluconazole on the disposition of phenytoin. Clin Pharmacol Ther 49:420-425.
10. Brøsen K and Gram LF (1989) Quinidine inhibits the 2-hydroxylation of imipramine and desipramine but not the demethylation of imipramine. Eur J Clin Pharmacol 37:155-160. (Pubitemid 19215455)
11. Brøsen K, Hansen JG, Nielsen KK, Sindrup SH, and Gram LF (1993) Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 44:349-355. (Pubitemid 23153452)
12. Brown HS, Ito K, Galetin A, and Houston JB (2005) Prediction of in vivo drug-drug interactions from in vitro data: impact of incorporating parallel pathways of drug elimination and inhibitor absorption rate constant. Br J Clin Pharmacol 60:508-518. (Pubitemid 41532451)
13. Burczynski FJ, Cai ZS, Moran JB, and Forker EL (1989) Palmitate uptake by cultured hepatocytes: albumin binding and stagnant layer phenomena. Am J Physiol 257:G584-G593.
14. Chung E, Nafziger AN, Kazierad DJ, and Bertino JS Jr (2006) Comparison of midazolam and simvastatin as cytochrome P450 3A probes. Clin Pharmacol Ther 79:350-361.
15. Cui Y and Walter B (2003) Influence of albumin binding on the substrate transport mediated by human hepatocyte transporters OATP2 and OATP8. J Gastroenterol 38:60-68. (Pubitemid 36267696)
16. Dayer P, Kronbach T, Eichelbaum M, and Meyer UA (1987) Enzymatic basis of the debrisoquine/sparteine-type genetic polymorphism of drug oxidation. Characterization of bufuralol 1′-hydroxylation in liver microsomes of in vivo phenotyped carriers of the genetic deficiency. Biochem Pharmacol 36:4145-4152. (Pubitemid 18010971)
17. DeWitte RS (2006) Avoiding physicochemical artefacts in early ADME-Tox experiments. Drug Discov Today 11:855-859.
18. Eap CB, Buclin T, Cucchia G, Zullino D, Hustert E, Bleiber G, Golay KP, Aubert AC, Baumann P, Telenti A, et al. (2004) Oral administration of a low dose of midazolam (75 μg) as an in vivo probe for CYP3A activity. Eur J Clin Pharmacol 60:237-246. (Pubitemid 38916442)
19. Einolf HJ (2007) Comparison of different approaches to predict metabolic drug-drug interactions. Xenobiotica 37:1257-1294.
20. Ernest CS 2nd, Hall SD, and Jones DR (2005) Mechanism-based inactivation of CYP3A by HIV protease inhibitors. J Pharmacol Exp Ther 312:583-591. (Pubitemid 40189555)
21. Fahmi OA, Hurst S, Plowchalk D, Cook J, Guo F, Youdim K, Dickins M, Phipps A, Darekar A, Hyland R, et al. (2009) Comparison of different algorithms for predicting clinical drug-drug interactions, based on the use of CYP3A4 in vitro data: predictions of compounds as precipitants of interaction. Drug Metab Dispos 37:1658-1666.
22. Fahmi OA, Maurer TS, Kish M, Cardenas E, Boldt S, and Nettleton D (2008) A combined model for predicting CYP3A4 clinical net drug-drug interaction based on CYP3A4 inhibition, inactivation, and induction determined in vitro. Drug Metab Dispos 36:1698-1708.
23. Forker EL, Luxon BA, Snell M, and Shurmantine WO (1982) Effect of albumin binding on the hepatic transport of rose bengal: surface-mediated dissociation of limited capacity. J Pharmacol Exp Ther 223:342-347. (Pubitemid 12005731)
24. Funck-Brentano C, Kroemer HK, Pavlou H, Woosley RL, and Roden DM (1989a) Genetically-determined interaction between propafenone and low dose quinidine: role of active metabolites in modulating net drug effect. Br J Clin Pharmacol 27:435-444. (Pubitemid 19101150)
25. Funck-Brentano C, Turgeon J, Woosley RL, and Roden DM (1989b) Effect of low dose quinidine on encainide pharmacokinetics and pharmacodynamics. Influence of genetic polymorphism. J Pharmacol Exp Ther 249:134-142.
26. Galetin A, Gertz M, and Houston JB (2008) Potential role of intestinal first-pass metabolism in the prediction of drug-drug interactions. Expert Opin Drug Metab Toxicol 4:909-922.
27. Goresky CA and Rose CP (1977) Blood-tissue exchange in liver and heart: the influence of heterogeneity of capillary transit times. Fed Proc 36:2629-2634. (Pubitemid 8216413)
28. Hallifax D, Galetin A, and Houston JB (2008) Prediction of metabolic clearance using fresh human hepatocytes: comparison with cryopreserved hepatocytes and hepatic microsomes for five benzodiazepines. Xenobiotica 38:353-367. (Pubitemid 351380282)
29. Hamelin BA, Bouayad A, Méthot J, Jobin J, Desgagnés P, Poirier P, Allaire J, Dumesnil J, and Turgeon J (2000) Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. Clin Pharmacol Ther 67:466-477. (Pubitemid 30327485)
30. Hansen JM, Kampmann JP, Siersbaek-Nielsen K, Lumholtz IB, Arrøe M, Abildgaard U, and Skovsted L (1979) The effect of different sulfonamides on phenytoin metabolism in man. Acta Med Scand Suppl 624:106-110. (Pubitemid 9126622)
31. Hardman JG, Limbird LE, and Gilman AG (2001) Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th ed, McGraw-Hill, New York.
32. Hemeryck A, Lefebvre RA, De Vriendt C, and Belpaire FM (2000) Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther 67:283-291. (Pubitemid 30176387)
33. Houston JB and Carlile DJ (1997) Prediction of hepatic clearance from microsomes, hepatocytes, and liver slices. Drug Metab Rev 29:891-922.
34. Ito K, Brown HS, and Houston JB (2003) Database analyses for the prediction of in vivo drug-drug interactions from in vitro data. Br J Clin Pharmacol 57:13.
35. Ito K, Iwatsubo T, Kanamitsu S, Ueda K, Suzuki H, and Sugiyama Y (1998) Prediction of pharmacokinetic alterations caused by drug-drug interactions: metabolic interaction in the liver. Pharmacol Rev 50:387-412.
36. Iwatsubo T, Hirota N, Ooie T, Suzuki H, and Sugiyama Y (1996) Prediction of in vivo drug disposition from in vitro data based on physiological pharmacokinetics. Biopharm Drug Dispos 17:273-310. (Pubitemid 26176731)
37. Johnson JA and Burlew BS (1996) Metoprolol metabolism via cytochrome P4502D6 in ethnic populations. Drug Metab Dispos 24:350-355. (Pubitemid 26087089)
38. Kantola T, Backman JT, Niemi M, Kivistö KT, and Neuvonen PJ (2000) Effect of fluconazole on plasma fluvastatin and pravastatin concentrations. Eur J Clin Pharmacol 56:225-229. (Pubitemid 30456682)
39. Kaukonen KM, Olkkola KT, and Neuvonen PJ (1998) Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174. Eur J Clin Pharmacol 53:445-449. (Pubitemid 28154745)
40. Kazierad DJ, Martin DE, Blum RA, Tenero DM, Ilson B, Boike SC, Etheredge R, and Jorkasky DK (1997) Effect of fluconazole on the pharmacokinetics of eprosartan and losartan in healthy male volunteers. Clin Pharmacol Ther 62:417-425. (Pubitemid 27475226)
41. Kharasch ED, Walker A, Hoffer C, and Sheffels P (2005) Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimally invasive and noninvasive probes for hepatic and first-pass CYP3A activity. J Clin Pharmacol 45:1187-1197. (Pubitemid 41361919)
42. Kurtz DL, Bergstrom RF, Goldberg MJ, and Cerimele BJ (1997) The effect of sertraline on the pharmacokinetics of desipramine and imipramine. Clin Pharmacol Ther 62:145-156. (Pubitemid 27373462)
43. Laine K, De Bruyn S, Björklund H, Rouru J, Hänninen J, Scheinin H, and Anttila M (2004) Effect of the novel anxiolytic drug deramciclane on cytochrome P(450) 2D6 activity as measured by desipramine pharmacokinetics. Eur J Clin Pharmacol 59:893-898. (Pubitemid 38333680)
44. Lam YW, Alfaro CL, Ereshefsky L, and Miller M (2003) Pharmacokinetic and pharmacodynamic interactions of oral midazolam with ketoconazole, fluoxetine, fluvoxamine, and nefazodone. J Clin Pharmacol 43:1274-1282. (Pubitemid 37280799)
45. Lazar JD and Wilner KD (1990) Drug interactions with fluconazole. Rev Infect Dis 12 (Suppl 3):S327-S333. (Pubitemid 20125728)
46. Li AP, Lu C, Brent JA, Pham C, Fackett A, Ruegg CE, and Silber PM (1999) Cryopreserved human hepatocytes: characterization of drug-metabolizing enzyme activities and applications in higher throughput screening assays for hepatotoxicity, metabolic stability, and drug-drug interaction potential. Chem Biol Interact 121:17-35. (Pubitemid 29240667)
47. Lu C, Berg C, Prakash SR, Lee FW, and Balani SK (2008a) Prediction of pharmacokinetic drug-drug interactions using human hepatocyte suspension in plasma and cytochrome P450 phenotypic data. III. In vitro-in vivo correlation with fluconazole. Drug Metab Dispos 36:1261-1266. (Pubitemid 351929309)
48. Lu C, Hatsis P, Berg C, Lee FW, and Balani SK (2008b) Prediction of pharmacokinetic drug-drug interactions using human hepatocyte suspension in plasma and cytochrome P450 phenotypic data. II. In vitro-in vivo correlation with ketoconazole. Drug Metab Dispos 36:1255-1260. (Pubitemid 351929308)
49. Lu C, Miwa GT, Prakash SR, Gan LS, and Balani SK (2007) A novel model for the prediction of drug-drug interactions in humans based on in vitro cytochrome p450 phenotypic data. Drug Metab Dispos 35:79-85. (Pubitemid 46043232)
50. Majumdar AK, McCrea JB, Panebianco DL, Hesney M, Dru J, Constanzer M, Goldberg MR, Murphy G, Gottesdiener KM, Lines CR, et al. (2003) Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe. Clin Pharmacol Ther 74:150-156. (Pubitemid 36951812)
51. Majumdar AK, Yan KX, Selverian DV, Barlas S, Constanzer M, Dru J, McCrea JB, Ahmed T, Frick GS, Kraft WK, et al. (2007) Effect of aprepitant on the pharmacokinetics of intravenous midazolam. J Clin Pharmacol 47:744-750. (Pubitemid 46800417)
52. Mankowski DC (1999) The role of CYP2C19 in the metabolism of (+/-) bufuralol, the prototypic substrate of CYP2D6. Drug Metab Dispos 27:1024-1028.
53. Mao J, Mohutsky MA, Harrelson JP, Wrighton SA, and Hall SD (2011) Prediction of CYP3A-mediated drug-drug interactions using human hepatocytes suspended in human plasma. Drug Metab Dispos 39:591-602.
54. Masuda K, Tamagake K, Okuda Y, Torigoe F, Tsuzuki D, Isobe T, Hichiya H, Hanioka N, Yamamoto S, and Narimatsu S (2005) Change in enantioselectivity in bufuralol 1″-hydroxylation by the substitution of phenylalanine-120 by alanine in cytochrome P450 2D6. Chirality 17:37-43. (Pubitemid 39665573)
55. McCrea J, Prueksaritanont T, Gertz BJ, Carides A, Gillen L, Antonello S, Brucker MJ, Miller-Stein C, Osborne B, and Waldman S (1999) Concurrent administration of the erythromycin breath test (EBT) and oral midazolam as in vivo probes for CYP3A activity. J Clin Pharmacol 39:1212-1220. (Pubitemid 30644001)
56. McGinnity DF, Tucker J, Trigg S, and Riley RJ (2005) Prediction of CYP2C9-mediated drug-drug interactions: a comparison using data from recombinant enzymes and human hepatocytes. Drug Metab Dispos 33:1700-1707. (Pubitemid 41539969)
57. Narimatsu S, Takemi C, Kuramoto S, Tsuzuki D, Hichiya H, Tamagake K, and Yamamoto S (2003) Stereoselectivity in the oxidation of bufuralol, a chiral substrate, by human cytochrome P450s. Chirality 15:333-339. (Pubitemid 36459440)
58. Niemi M, Backman JT, Neuvonen M, Laitila J, Neuvonen PJ, and Kivistö KT (2001) Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. Clin Pharmacol Ther 69:194-200. (Pubitemid 32382501)
59. O'Reilly RA, Goulart DA, Kunze KL, Neal J, Gibaldi M, Eddy AC, and Trager WF (1992) Mechanisms of the stereoselective interaction between miconazole and racemic warfarin in human subjects. Clin Pharmacol Ther 51:656-667.
60. Obach RS, Walsky RL, Venkatakrishnan K, Gaman EA, Houston JB, and Tremaine LM (2006) The utility of in vitro cytochrome P450 inhibition data in the prediction of drug-drug interactions. J Pharmacol Exp Ther 316:336-348. (Pubitemid 41832613)
61. Ockner RK, Weisiger RA, and Gollan JL (1983) Hepatic uptake of albumin-bound substances: albumin receptor concept. Am J Physiol 245:G13-G18. (Pubitemid 14227197)
62. Olkkola KT, Ahonen J, and Neuvonen PJ (1996) The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Anesth Analg 82:511-516. (Pubitemid 26072953)
63. Olkkola KT, Backman JT, and Neuvonen PJ (1994) Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 55:481-485. (Pubitemid 24192233)
64. Palmgrén JJ, Mönkkönen J, Korjamo T, Hassinen A, and Auriola S (2006) Drug adsorption to plastic containers and retention of drugs in cultured cells under in vitro conditions. Eur J Pharm Biopharm 64:369-378. (Pubitemid 44585210)
65. Preskorn SH, Alderman J, Chung M, Harrison W, Messig M, and Harris S (1994) Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine. J Clin Psychopharmacol 14:90-98. (Pubitemid 24120706)
66. Reed RG (1977) Kinetics of bilirubin binding to bovine serum albumin and the effects of palmitate. J Biol Chem 252:7483-7487.
67. Rostami-Hodjegan A and Tucker G (2004) 'In silico' simulations to assess the 'in vivo' consequences of 'in vitro' metabolic drug-drug interactions. Drug Discov Today 1:441-448. (Pubitemid 40186348)
68. Saari TI, Laine K, Leino K, Valtonen M, Neuvonen PJ, and Olkkola KT (2006) Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Clin Pharmacol Ther 79:362-370.
69. Sharma A, Pibarot P, Pilote S, Dumesnil JG, Arsenault M, Bélanger PM, Meibohm B, and Hamelin BA (2005) Modulation of metoprolol pharmacokinetics and hemodynamics by diphenhydramine coadministration during exercise testing in healthy premenopausal women. J Pharmacol Exp Ther 313:1172-1181. (Pubitemid 40727020)
70. Skinner MH, Kuan HY, Pan A, Sathirakul K, Knadler MP, Gonzales CR, Yeo KP, Reddy S, Lim M, Ayan-Oshodi M, et al. (2003) Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther 73:170-177. (Pubitemid 36269668)
71. Svenson A, Holmer E, and Andersson LO (1974) A new method for the measurement of dissociation rates for complexes between small ligands and proteins as applied to the palmitate and bilirubin complexes with serum albumin. Biochim Biophys Acta 342:54-59.
72. Tang C, Lin Y, Rodrigues AD, and Lin JH (2002) Effect of albumin on phenytoin and tolbutamide metabolism in human liver microsomes: an impact more than protein binding. Drug Metab Dispos 30:648-654. (Pubitemid 34579097)
73. Touchette MA, Chandrasekar PH, Milad MA, and Edwards DJ (1992) Contrasting effects of fluconazole and ketoconazole on phenytoin and testosterone disposition in man. Br J Clin Pharmacol 34:75-78.
74. Tsunoda SM, Velez RL, von Moltke LL, and Greenblatt DJ (1999) Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: effect of ketoconazole. Clin Pharmacol Ther 66:461-471.
75. Turgeon J, Fiset C, Giguère R, Gilbert M, Moerike K, Rouleau JR, Kroemer HK, Eichelbaum M, Grech-Bélanger O, and Bélanger PM (1991) Influence of debrisoquine phenotype and of quinidine on mexiletine disposition in man. J Pharmacol Exp Ther 259:789-798.
76. Turgeon J, Pavlou HN, Wong W, Funck-Brentano C, and Roden DM (1990) Genetically determined steady-state interaction between encainide and quinidine in patients with arrhythmias. J Pharmacol Exp Ther 255:642-649.
77. Vandenbrink BM, Foti RS, Rock DA, Wienkers LC, and Wahlstrom JL (2012) Prediction of CYP2D6 drug interactions from in vitro data: evidence for substrate-dependent inhibition. Drug Metab Dispos 40:47-53.
78. Veronese ME, Miners JO, Randles D, Gregov D, and Birkett DJ (1990) Validation of the tolbutamide metabolic ratio for population screening with use of sulfaphenazole to produce model phenotypic poor metabolizers. Clin Pharmacol Ther 47:403-411. (Pubitemid 20115029)
79. Wang YH, Jones DR, and Hall SD (2004) Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites. Drug Metab Dispos 32:259-266. (Pubitemid 38176944)
80. Weisiger R, Gollan J, and Ockner R (1981) Receptor for albumin on the liver cell surface may mediate uptake of fatty acids and other albumin-bound substances. Science 211:1048-1051.
81. Wilkinson GR (1987) Clearance approaches in pharmacology. Pharmacol Rev 39:1-47.
82. Xu L, Chen Y, Pan Y, Skiles GL, and Shou M (2009) Prediction of human drug-drug interactions from time-dependent inactivation of CYP3A4 in primary hepatocytes using a population-based simulator. Drug Metab Dispos 37:2330-2339.
83. Zhao P, Kunze KL, and Lee CA (2005) Evaluation of time-dependent inactivation of CYP3A in cryopreserved human hepatocytes. Drug Metab Dispos 33:853-861. (Pubitemid 40686640)
84. Zussman BD, Davie CC, and Fowles SE (1995) Sertraline, like other SSRIs, is a significant inhibitor of desipramine metabolism in vivo (Abstract). Br J Clin Pharmacol 39:550P-1.