Quantification of human hepatocyte cytochrome P450 enzymes and transporters induced by HIV protease inhibitors using newly validated LC-MS/MS cocktail assays and RT-PCR

Biopharmaceutics and Drug Disposition

Volumn 33, Issue 4, 2012, Pages 207-217

  Liu, Li ^a   Mugundu, Ganesh M ^b   Kirby, Brian J ^a   Samineni, Divya ^b   Desai, Pankaj B ^b   Unadkat, Jashvant D ^a  

^a UNIVERSITY OF WASHINGTON   (United States)

^b UNIVERSITY OF CINCINNATI   (United States)

Author keywords

CYP450 induction; DDI prediction; drug drug interactions; HIV protease inhibitors; human hepatocytes; human immunodeficiency virus (HIV) medications; LC MS MS cocktail assays; transporter induction

Indexed keywords

AMPRENAVIR; ATAZANAVIR; CYTOCHROME P450 1A; CYTOCHROME P450 2A6; CYTOCHROME P450 2B6; CYTOCHROME P450 2C19; CYTOCHROME P450 2C8; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 2E1; CYTOCHROME P450 3A; INDINAVIR; LOPINAVIR; MESSENGER RNA; MULTIDRUG RESISTANCE PROTEIN 1; MULTIDRUG RESISTANCE PROTEIN 2; MULTIDRUG RESISTANCE PROTEIN 4; NELFINAVIR; ORGANIC ANION TRANSPORTER; ORGANIC ANION TRANSPORTER 1; ORGANIC ANION TRANSPORTER 1B3; ORGANIC ANION TRANSPORTER 2; RITONAVIR; SAQUINAVIR; TIPRANAVIR; UNCLASSIFIED DRUG;

ADOLESCENT; ADULT; AGED; ARTICLE; CONTROLLED STUDY; ENZYME ACTIVITY; ENZYME INDUCTION; FEMALE; HUMAN; HUMAN CELL; LIQUID CHROMATOGRAPHY; LIVER CELL; MALE; PROTEIN EXPRESSION; PROTEIN INDUCTION; QUANTITATIVE ANALYSIS; REAL TIME POLYMERASE CHAIN REACTION; TANDEM MASS SPECTROMETRY; VALIDATION PROCESS;

ADOLESCENT; ADULT; AGED; CHROMATOGRAPHY, LIQUID; CYTOCHROME P-450 ENZYME SYSTEM; ENZYME INDUCTION; FEMALE; GENE EXPRESSION REGULATION; HEPATOCYTES; HIV PROTEASE INHIBITORS; HUMANS; MALE; MEMBRANE TRANSPORT PROTEINS; MICROSOMES, LIVER; MIDDLE AGED; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; RNA, MESSENGER; TANDEM MASS SPECTROMETRY;

EID: 84861231597     PISSN: 01422782     EISSN: 1099081X     Source Type: Journal    
DOI: 10.1002/bdd.1788     Document Type: Article

References (37)

1. Unadkat JD, Wang Y,. Antivirals. In Metabolic Drug Interaction, Levy RH, Trager WF, Hansten PD, Eichelbaum M, (eds). Lippincott Williams & Wilkins: Philadelphia, 2000; 421-433.
2. Ernest CS 2nd, Hall SD, Jones DR,. Mechanism-based inactivation of CYP3A by HIV protease inhibitors. J Pharmacol Exp Ther 2005; 312: 583-591. (Pubitemid 40189555)
3. Buss N, Snell P, Bock J, Hsu A, Jorga K,. Saquinavir and ritonavir pharmacokinetics following combined ritonavir and saquinavir (soft gelatin capsules) administration. J Clin Pharmacol 2001; 52: 255-264. (Pubitemid 33796222)
4. Boffito M, Dickinson L, Hill A, et al,. Steady-state pharmacokinetics of saquiniavir hard-gel/ritonavir/foxamprenavir in HIV-1-infected patients. J Acquir Immune Defic Syndr 2004; 37: 1376-1384. (Pubitemid 39435052)
5. Kirby BJ, Collier AC, Kharasch ED, Whittington D, Thummel KE, Unadkat JD,. Complex drug interactions of HIV protease inhibitors 1: inactivation, induction, and inhibition of cytochrome P450 3A by ritonavir or nelfinavir. Drug Metab Dispos 2011; 39: 1070-1078.
6. Dixit V, Hariparsad N, Li F, Desai P, Thummel KE, Unadkat JD,. Cytochrome P450 enzymes and transporters induced by anti-human immunodeficiency virus protease inhibitors in human hepatocytes: implications for predicting clinical drug interactions. Drug Metab Dispos 2007; 35: 1853-1859. (Pubitemid 47481578)
7. Paine MF, Khalighi M, Fisher JM, et al,. Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. J Pharmacol Exp Ther 1997; 283: 1552-1562. (Pubitemid 28016533)
8. The FDA website.
9. Dixit V, Hariparsad N, Desai P, Unadkat JD,. In vitro LC-MS cocktail assays to determine simultaneously human cytochrome P450 activities. Biopharm Drug Dispos 2007; 28: 257-262. (Pubitemid 47180175)
10. Desai PB, Nallani SC, Sane RS, et al,. Induction of cytochrome P450 3A4 in primary human hepatocytes and activation of the human pregnane X receptor by tamoxifen and 4-hydroxytamoxifen. Drug Metab Dispos 2002; 30: 608-612. (Pubitemid 34456986)
11. Ozdemir V, Kalow W, Tang BK, et al,. Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method. Pharmacogenetics 2000; 10: 373-388. (Pubitemid 30433571)
12. Fahmi OA, Kish M, Boldt S, Obach RS,. Cytochrome P450 3A4 mRNA is a more reliable marker than CYP3A4 activity for detecting pregnane X receptor-activated induction of drug-metabolizing enzymes. Drug Metab Dispos 2010; 38: 1605-1611.
13. Mugundu GM, Hariparsad N, Desai PB,. Impact of ritonavir, atazanavir and their combination on the CYP3A4 induction by efavirenz in primary human hepatocytes. Drug Metab Lett 2010; 4: 45-50.
14. The FDA website.
15. Brophy DF, Israel DS, Pastor A, et al,. Pharmacokinetic interaction between amprenavir and clarithromycin in healthy male volunteers. Antimicrob Agents Chemother 2000; 44: 978-984. (Pubitemid 30165279)
16. Hsyu PH, Lillibridge J, Daniels E, Kerr BM,. Pharmacokinetic interaction of nelfinavir and methadone in intravenous drug users. Biopharm Drug Dispos 2006; 27: 61-68.
17. Hogeland GW, Swindells S, McNabb JC, Kashuba AD, Yee GC, Lindley CM,. Lopinavir/ritonavir reduces bupropion plasma concentrations in healthy subjects. Clin Pharmacol Ther 2007; 81: 69-75. (Pubitemid 46069599)
18. Mukwaya G, MacGregor T, Hoelscher D, et al,. Interaction of ritonavir-boosted tipranavir with loperamide does not result in loperamide-associated neurologic side effects in healthy volunteers. Antimicrob Agents Chemother 2005; 49: 4903-4910. (Pubitemid 41778900)
19. Lim ML, Min SS, Eron JJ, et al,. Coadministration of lopinavir/ritonavir and phenytoin results in two-way drug interaction through cytochrome P-450 induction. J Acquir Immune Defic Syndr 2004; 36: 1034-1040. (Pubitemid 38989369)
20. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al,. NIAID AIDS Clinical Trials Group. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS 2002; 16: 569-577. (Pubitemid 34218852)
21. Wyen C, Fuhr U, Frank D, et al,. Effect of an antiretroviral regimen containing ritonavir boosted lopinavir on intestinal and hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected patients. Clin Pharmacol Ther 2008; 84: 75-82. (Pubitemid 351861487)
22. Kharasch ED, Hoffer C, Whittington D, Walker A, Bedynek PS,. Methadone pharmacokinetics are independent of cytochrome P4503A (CYP3A) activity and gastrointestinal drug transport: insights from methadone interactions with ritonavir/indinavir. Anesthesiology 2009; 110: 660-672.
23. Busti AJ, Bain AM, Hall RG, et al,. Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin. J Cardiovasc Pharmacol 2008; 51: 605-610.
24. Kiser JJ, Gerber JG, Predhomme JA, Wolfe P, Flynn DM, Hoody DW,. Drug/drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr 2008; 47: 570-578. (Pubitemid 351442013)
25. Annaert P, Ye ZW, Stieger B, Augustijns P,. Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1. Xenobiotica 2010; 40: 163-176.
26. Hsiao P, Bui T, Ho RJ, Unadkat JD,. In vitro-to-in vivo prediction of p-glycoprotein-based drug interactions at the human and rodent blood-brain barrier. Drug Metab Dispos 2008; 36: 481-484. (Pubitemid 351397990)
27. Kirby BJ, Collier AC, Kharasch ED, et al,. Complex drug interactions of HIV protease inhibitors 2: In vivo induction and in vitro to in vivo correlation of induction of cytochrome P450 1A2, 2B6 and 2C9 by ritonavir or nelfinavir. Drug Metab Dispos 2011; 39: 2329-2337.
28. Wood R, Eron J, Arasteh K, et al,. A 42-week open-label study to assess the pharmacokinetics, antiretroviral activity, and safety of amprenavir or amprenavir plus ritonavir in combination with abacavir and lamivudine for treatment of HIV-infected patients. Clin Infect Dis 2004; 39: 591-594. (Pubitemid 39120942)
29. Atazanavir sulfate (Reyataz) drug label. Bristol-Myers Squibb, October 2004.
30. Saah AJ, Winchell GA, Nessly ML, Seniuk MA, Rhodes RR, Deutsch PJ,. Pharmacokinetic profile and tolerability of indinavir-ritonavir combinations in healthy volunteers. Antimicrob Agents Chemother 2001; 45: 2710-2715. (Pubitemid 32906661)
31. Amsden GW, Nafziger AN, Foulds G, Cabelus LJ,. A study of the pharmacokinetics of azithromycin and nelfinavir when coadministered in healthy volunteers. J Clin Pharmacol 2000; 40: 1522-1527.
32. la Porte CJ, de Graaff-Teulen MJ, Colbers EP, et al,. Effect of efavirenz treatment on the pharmacokinetics of nelfinavir boosted by ritonavir in healthy volunteers. Br J Clin Pharmacol 2004; 58: 632-640. (Pubitemid 39665150)
33. Saquinavir (Fortovase) soft gelatin capsules drug label. Hoffmann-Lab Roche, December 2003.
34. Kurowski M, Sternfeld T, Sawyer A, Hill A, Möcklinghoff C,. Pharmacokinetic and tolerability profile of twice-daily saquinavir hard gelatin capsules and saquinavir soft gelatin capsules boosted with ritonavir in healthy volunteers. HIV Med 2003; 4: 94-100. (Pubitemid 36582291)
35. Hardman JG, Limbird LE, Gilman AG,. Goodman & Gilman's The Pharmacological Basis of Therapeutics (10th edn. edn). McGraw-Hill: New York, 2001.
36. Klein CE, Chiu YL, Cai Y, et al,. Effects of acid-reducing agents on the pharmacokinetics of lopinavir/ritonavir and ritonavir-boosted atazanavir. J Clin Pharmacol 2008; 48: 553-562. (Pubitemid 351503512)
37. Mathias AA, Hinkle J, Shen G, et al,. Effect of ritonavir-boosted tipranavir or darunavir on the steady-state pharmacokinetics of elvitegravir. J Acquir Immune Defic Syndr 2008; 49: 156-162.