Skip to main content

Advertisement

SpringerLink
Log in

Influence of chronic hepatitis C infection on cytochrome P450 3a4 activity using midazolam as an in vivo probe substrate

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Inflammation-related changes in pharmacokinetics have been described for a number of disease-states including cancer, infection, and autoimmune disorders. This study examined the impact of chronic hepatitis C infection (CHC) on the pharmacokinetics of the cytochrome P450 3A probe midazolam in patients without significant liver disease who were either treatment naïve or prior interferon null-responders.

Methods

Data were pooled from three studies which compared the pharmacokinetics of oral midazolam in healthy volunteers (n = 107) and in treatment-naive patients (n = 35) and interferon-null responders (n = 24) with CHC but without significant liver disease. Oral midazolam was administered as a single 2 mg oral dose, followed by frequent pharmacokinetic sampling and determination of the pharmacokinetics of midazolam and its α-hydroxy metabolite. CYP3A activity was determined by the metabolic ratio (MR) of the AUC metabolite/AUC parent and compared across groups as the mean effect ratio (test/reference).

Results

The midazolam MR was lower in treatment-naïve patients with CHC than in health volunteers with a mean effect ratio of 0.63 [90 % confidence interval (CI) 0.56–0.72]. The effect was more pronounced in null-responders, who demonstrated a mean MR effect ratio of 0.46 (90 % CI 0.39–0.53) compared to volunteers. The mean area under the concentration–time curve (AUCinf) for midazolam in healthy volunteers, naïve patients, and null-responders was 32.3 [coefficient of variation (CV%) 41], 36.5 (CV% 33.5), and 55.3 (CV% 36.9) ng.h/mL, respectively.

Conclusions

The results of this study demonstrate a reduction in CYP3A4 activity between healthy volunteers and patients with CHC, with interferon null-responders demonstrating the most substantial difference. These results may have implications for the pharmacotherapy of patients infected with CHC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Jones AE, Brown KC, Werner RE, Gotzkowsky K, Gaedigk A, Blake M, Hein DW, van der Horst C, Kashuba AD (2010) Variability in drug metabolizing enzyme activity in HIV-infected patients. Eur J Clin Pharmacol 66(5):475–485

    Article  PubMed  CAS  Google Scholar 

  2. Ince I, de Wildt SN, Peeters MY, Murry DJ, Tibboel D, Danhof M, Knibbe CA (2012) Critical illness is a major determinant of midazolam clearance in children aged 1 month to 17 years. Ther Drug Monit 34(4):381–389

    Article  PubMed  CAS  Google Scholar 

  3. Kacevska M, Robertson GR, Clarke SJ, Liddle C (2008) Inflammation and CYP3A4-mediated drug metabolism in advanced cancer: impact and implications for chemotherapeutic drug dosing. Expert Opin Drug Metab Toxicol 4(2):137–149

    Article  PubMed  CAS  Google Scholar 

  4. Shelly MP, Mendel L, Park GR (1987) Failure of critically ill patients to metabolise midazolam. Anaesthesia 42(6):619–626

    Article  PubMed  CAS  Google Scholar 

  5. Walker SB, Middelkamp JN (1982) Theophylline toxicity and viral infections. Pediatrics 70(3):508–509

    Google Scholar 

  6. Mayo PR, Skeith K, Russell AS, Jamali F (2000) Decreased dromotropic response to verapamil despite pronounced increased drug concentration in rheumatoid arthritis. Br J Clin Pharmacol 50(6):605–613

    Article  PubMed  CAS  Google Scholar 

  7. Schmitt C, Kuhn B, Zhang X, Kivitz AJ, Grange S (2011) Disease-drug-drug interaction involving tocilizumab and simvastatin in patients with rheumatoid arthritis. Clin Pharmacol Ther 89(5):735–740

    Article  PubMed  CAS  Google Scholar 

  8. Abdel-Razzak Z, Loyer P, Fautrel A, Gautier JC, Corcos L, Turlin B, Beaune P, Guillouzo A (1993) Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture. Mol Pharmacol 44(4):707–715

    PubMed  CAS  Google Scholar 

  9. Ding X, Staudinger JL (2005) Repression of PXR-mediated induction of hepatic CYP3A gene expression by protein kinase C. Biochem Pharmacol 69(5):867–873

    Article  PubMed  CAS  Google Scholar 

  10. Muntane-Relat J, Ourlin JC, Domergue J, Maurel P (1995) Differential effects of cytokines on the inducible expression of CYP1A1, CYP1A2, and CYP3A4 in human hepatocytes in primary culture. Hepatology 22(4 Pt 1):1143–1153

    Article  PubMed  CAS  Google Scholar 

  11. Sunman JA, Hawke RL, LeCluyse EL, Kashuba AD (2004) Kupffer cell-mediated IL-2 suppression of CYP3A activity in human hepatocytes. Drug Metab Dispos 32(3):359–363

    Article  PubMed  CAS  Google Scholar 

  12. Tinel M, Elkahwaji J, Robin MA, Fardel N, Descatoire V, Haouzi D, Berson A, Pessayre D (1999) Interleukin-2 overexpresses c-myc and down-regulates cytochrome P-450 in rat hepatocytes. J Pharmacol Exp Ther 289(2):649–655

    PubMed  CAS  Google Scholar 

  13. Tinel M, Robin MA, Doostzadeh J, Maratrat M, Ballet F, Fardel N, el Kahwaji J, Beaune P, Daujat M, Labbe G et al (1995) The interleukin-2 receptor down-regulates the expression of cytochrome P450 in cultured rat hepatocytes. Gastroenterology 109(5):1589–1599

    Article  PubMed  CAS  Google Scholar 

  14. Renton KW (2005) Regulation of drug metabolism and disposition during inflammation and infection. Expert Opin Drug Metab Toxicol 1(4):629–640

    Article  PubMed  CAS  Google Scholar 

  15. Dickinson L, Khoo S, Back D (2008) Differences in the pharmacokinetics of protease inhibitors between healthy volunteers and HIV-infected persons. Curr Opin HIV AIDS 3(3):296–305

    Article  PubMed  Google Scholar 

  16. Grub S, Bryson H, Goggin T, Ludin E, Jorga K (2001) The interaction of saquinavir (soft gelatin capsule) with ketoconazole, erythromycin and rifampicin: comparison of the effect in healthy volunteers and in HIV-infected patients. Eur J Clin Pharmacol 57(2):115–121

    Article  PubMed  CAS  Google Scholar 

  17. Smith PF, DiCenzo R, Morse GD (2001) Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors. Clin Pharmacokinet 40(12):893–905

    Article  PubMed  CAS  Google Scholar 

  18. Smith PF, Robbins GK, Shafer RW, Wu H, Yu S, Hirsch MS, Merigan TC, Park JG, Forrest A, Fischl MA, Morse GD (2005) Pharmacokinetics of nelfinavir and efavirenz in antiretroviral-naive, human immunodeficiency virus-infected subjects when administered alone or in combination with nucleoside analog reverse transcriptase inhibitors. Antimicrob Agents Chemother 49(8):3558–3561

    Article  PubMed  CAS  Google Scholar 

  19. Jetter A, Fatkenheuer G, Frank D, Klaassen T, Seeringer A, Doroshyenko O, Kirchheiner J, Hein W, Schomig E, Fuhr U, Wyen C (2010) Do activities of cytochrome P450 (CYP)3A, CYP2D6 and P-glycoprotein differ between healthy volunteers and HIV-infected patients? Antivir Ther 15(7):975–983

    Article  PubMed  CAS  Google Scholar 

  20. Chang KC, Bell TD, Lauer BA, Chai H (1978) Altered theophylline pharmacokinetics during acute respiratory viral illness. Lancet 1(8074):1132–1133

    Article  PubMed  CAS  Google Scholar 

  21. Burnett DA, Barak AJ, Tuma DJ, Sorrell MF (1976) Altered elimination of antipyrine in patients with acute viral hepatitis. Gut 17(5):341–344

    Article  PubMed  CAS  Google Scholar 

  22. Brainard DM, Petry A, Anderson MS, Mitselos A, Laethem T, Heirman I, Caro L, Stone JA, Sun P, Panorchan P, Van Bortel LM, Iwamoto M, Wagner JA (2010) Safety, tolerability, and pharmacokinetics alter single and multiple doses of Mk-5172, a novel Hcv Ns3/4a protease inhibitor with potent activity against known resistance mutants, in healthy subjects. Hepatology 52(4):1216a–1217a

    Article  Google Scholar 

  23. Gane EJ, Roberts SK, Stedman CA, Angus PW, Ritchie B, Elston R, Ipe D, Morcos PN, Baher L, Najera I, Chu T, Lopatin U, Berrey MM, Bradford W, Laughlin M, Shulman NS, Smith PF (2010) Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 376(9751):1467–1475

    Article  PubMed  CAS  Google Scholar 

  24. Goldwater R, DeMicco MP, Zong JA, Chittick GE, Yuen GJ, West S, Kagel J, Bae A, Mo HM, Oldach D, Delaney WE, Findlay JW (2010) Safety, Pharmacokinetics, and Antiviral Activity of Single Oral Doses of the Hcv Ns3 Protease Inhibitor Gs 9256. Hepatology 52(4):717a–718a

    Google Scholar 

  25. Reesink HW, Fanning GC, Farha KA, Weegink C, Van Vliet A, Van 't Klooster G, Lenz O, Aharchi F, Marien K, Van Remoortere P, de Kock H, Broeckaert F, Meyvisch P, Van Beirendonck E, Simmen K, Verloes R (2010) Rapid HCV-RNA decline with once daily TMC435: a phase I study in healthy volunteers and hepatitis C patients. Gastroenterology 138(3):913–921

    Article  PubMed  CAS  Google Scholar 

  26. Wolffenbuttel L, Poli DD, Manfro RC, Goncalves LF (2004) Cyclosporine pharmacokinetics in anti-HCV + patients. Clin Transplant 18(6):654–660

    Article  PubMed  Google Scholar 

  27. Regazzi M, Maserati R, Villani P, Cusato M, Zucchi P, Briganti E, Roda R, Sacchelli L, Gatti F, Delle Foglie P, Nardini G, Fabris P, Mori F, Castelli P, Testa L (2005) Clinical pharmacokinetics of nelfinavir and its metabolite M8 in human immunodeficiency virus (HIV)-positive and HIV-hepatitis C virus-coinfected subjects. Antimicrob Agents Chemother 49(2):643–649

    Article  PubMed  CAS  Google Scholar 

  28. Dominguez S, Ghosn J, Peytavin G, Guiguet M, Tubiana R, Valantin MA, Murphy R, Bricaire F, Benhamou Y, Katlama C (2010) Impact of hepatitis C and liver fibrosis on antiretroviral plasma drug concentrations in HIV-HCV co-infected patients: the HEPADOSE study. J Antimicrob Chemother 65(11):2445–2449

    Article  PubMed  CAS  Google Scholar 

  29. Lauer GM, Walker BD (2001) Hepatitis C virus infection. N Engl J Med 345(1):41–52

    Article  PubMed  CAS  Google Scholar 

  30. Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH (2000) Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Intern Med 132(4):296–305

    Article  PubMed  CAS  Google Scholar 

  31. Guzman-Fulgencio M, Jimenez JL, Berenguer J, Fernandez-Rodriguez A, Lopez JC, Cosin J, Miralles P, Micheloud D, Munoz-Fernandez MA, Resino S (2012) Plasma IL-6 and IL-9 predict the failure of interferon-alpha plus ribavirin therapy in HIV/HCV-coinfected patients. J Antimicrob Chemother 67(5):1238–1245

    Article  PubMed  CAS  Google Scholar 

  32. Ueyama M, Nakagawa M, Sakamoto N, Onozuka I, Funaoka Y, Watanabe T, Nitta S, Kiyohashi K, Kitazume A, Murakawa M, Nishimura-Sakurai Y, Sekine-Osajima Y, Itsui Y, Azuma S, Kakinuma S, Watanabe M (2011) Serum interleukin-6 levels correlate with resistance to treatment of chronic hepatitis C infection with pegylated-interferon-alpha2b plus ribavirin. Antivir Ther 16(7):1081–1091

    Article  PubMed  CAS  Google Scholar 

  33. Aitken AE, Morgan ET (2007) Gene-specific effects of inflammatory cytokines on cytochrome P450 2C, 2B6 and 3A4 mRNA levels in human hepatocytes. Drug Metab Dispos 35(9):1687–1693

    Article  PubMed  CAS  Google Scholar 

  34. Jover R, Bort R, Gomez-Lechon MJ, Castell JV (2002) Down-regulation of human CYP3A4 by the inflammatory signal interleukin-6: molecular mechanism and transcription factors involved. FASEB J 16(13):1799–1801

    PubMed  CAS  Google Scholar 

  35. Watkins PB (1994) Noninvasive tests of CYP3A enzymes. Pharmacogenetics 4(4):171–184

    Article  PubMed  CAS  Google Scholar 

  36. Gane EJ, Rouzier R, Stedman C, Wiercinska-Drapalo A, Horban A, Chang L, Zhang Y, Sampeur P, Najera I, Smith P, Shulman NS, Tran JQ (2011) Antiviral activity, safety, and pharmacokinetics of danoprevir/ritonavir plus PEG-IFN alpha-2a/RBV in hepatitis C patients. J Hepatol 55(5):972–979

    Article  PubMed  CAS  Google Scholar 

  37. Huang SM, Strong JM, Zhang L, Reynolds KS, Nallani S, Temple R, Abraham S, Habet SA, Baweja RK, Burckart GJ, Chung S, Colangelo P, Frucht D, Green MD, Hepp P, Karnaukhova E, Ko HS, Lee JI, Marroum PJ, Norden JM, Qiu W, Rahman A, Sobel S, Stifano T, Thummel K, Wei XX, Yasuda S, Zheng JH, Zhao H, Lesko LJ (2008) New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters, and the guidance process. J Clin Pharmacol 48(6):662–670

    Article  PubMed  CAS  Google Scholar 

  38. Marbury TC, Ngo PL, Shadle CR, Jin B, Panebianco D, Caro L, Valentine J, Murphy G (2011) Pharmacokinetics of oral dexamethasone and midazolam when administered with single-dose intravenous 150 mg fosaprepitant in healthy adult subjects. J Clin Pharmacol 51(12):1712–1720

    Article  PubMed  CAS  Google Scholar 

  39. Lam YW, Alfaro CL, Ereshefsky L, Miller M (2003) Pharmacokinetic and pharmacodynamic interactions of oral midazolam with ketoconazole, fluoxetine, fluvoxamine, and nefazodone. J Clin Pharmacol 43(11):1274–1282

    Article  PubMed  CAS  Google Scholar 

  40. Latorre A, Morales E, Gonzalez E, Herrero JC, Ortiz M, Sierra P, Dominguez-Gil B, Torres A, Munoz MA, Andres A, Manzanares C, Morales JM (2002) Clinical management of renal transplant patients with hepatitis C virus infection treated with cyclosporine or tacrolimus. Transplant Proc 34(1):63–64

    Article  PubMed  CAS  Google Scholar 

  41. Petry AS, Fraser IP, Van Dyck K, Nachbar RB, De Lepeleire I, Robberechts M, Han L, Palcza J, Moiseev VS, Kobalava ZD, Uhle M, Wagner F, O'Mara E, Wagner JA (2011) Safety and antiviral activity of MK-5172, a next generation HCV NS3/4a protease inhibitor with a broad HCV genotypic activity spectrum and potent activity against known resistance mutants, in genotype 1 and 3 HCV-infected patients. Hepatology 52(4)

  42. Vee ML, Lecureur V, Stieger B, Fardel O (2009) Regulation of drug transporter expression in human hepatocytes exposed to the proinflammatory cytokines tumor necrosis factor-alpha or interleukin-6. Drug Metab Dispos 37(3):685–693

    Article  PubMed  Google Scholar 

  43. Basu A, Meyer K, Lai KK, Saito K, Di Bisceglie AM, Grosso LE, Ray RB, Ray R (2006) Microarray analyses and molecular profiling of Stat3 signaling pathway induced by hepatitis C virus core protein in human hepatocytes. Virology 349(2):347–358

    Article  PubMed  CAS  Google Scholar 

  44. Feld JJ, Nanda S, Huang Y, Chen W, Cam M, Pusek SN, Schweigler LM, Theodore D, Zacks SL, Liang TJ, Fried MW (2007) Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response. Hepatology 46(5):1548–1563

    Article  PubMed  CAS  Google Scholar 

  45. Schaefer CJ, Kossen K, Lim SR, Lin JH, Pan L, Bradford W, Smith PF, Seiwert SD (2011) Danoprevir monotherapy decreases inflammatory markers in patients with chronic hepatitis C virus infection. Antimicrob Agents Chemother 55(7):3125–3132

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors are indebted to Edward Gane, Catherine Stedman, Dennis Riff, and Thomas Hunt for participating in the success of the clinical trials, in addition to the site investigational staff and, most importantly, the patients and volunteers. The funding for this work was provided by Roche.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Pharma Research and Early Development, Roche, Inc., Nutley, NJ, USA

    P. N. Morcos, S. A. Moreira & B. J. Brennan

  2. Department of Biometrics, Pharma Development, Roche, Inc., Nutley, NJ, USA

    S. Blotner

  3. Virology, Pharma Development, Roche, Inc., South San Francisco, CA, USA

    N. S. Shulman

  4. Department of Pharmacy Practice, University at Buffalo School of Pharmacy, Kapoor Hall, Buffalo, NY, 14215, USA

    P. F. Smith

  5. d3 Medicine, Montville, NJ, USA

    P. F. Smith

Authors
  1. P. N. Morcos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. A. Moreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. J. Brennan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Blotner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N. S. Shulman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P. F. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. F. Smith.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morcos, P.N., Moreira, S.A., Brennan, B.J. et al. Influence of chronic hepatitis C infection on cytochrome P450 3a4 activity using midazolam as an in vivo probe substrate. Eur J Clin Pharmacol 69, 1777–1784 (2013). https://doi.org/10.1007/s00228-013-1525-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-013-1525-5

Keywords

Search

Navigation