Skip to main content
SpringerLink
Log in

Voriconazole greatly increases the exposure to oral buprenorphine

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

Abstract

Purpose

Buprenorphine has low oral bioavailability. Regardless of sublingual administration, a notable part of buprenorphine is exposed to extensive first-pass metabolism by the cytochrome P450 (CYP) 3A4. As drug interaction studies with buprenorphine are limited, we wanted to investigate the effect of voriconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics and pharmacodynamics of oral buprenorphine.

Methods

Twelve healthy volunteers were given either placebo or voriconazole (orally, 400 mg twice on day 1 and 200 mg twice on days 2–5) for 5 days in a randomized, cross-over study. On day 5, they ingested 0.2 mg (3.6 mg during placebo phase) oral buprenorphine. We measured plasma and urine concentrations of buprenorphine and norbuprenorphine and monitored their pharmacological effects. Pharmacokinetic parameters were normalized for a buprenorphine dose of 1.0 mg.

Results

Voriconazole greatly increased the mean area under the plasma concentration–time curve (AUC0–18) of buprenorphine (4.3-fold, P < 0.001), its peak concentration (Cmax) (3.9-fold), half-life (P < 0.05), and excretion into urine (Ae; P < 0.001). Voriconazole also markedly enhanced the Cmax (P < 0.001), AUC0–18 (P < 0.001), and Ae (P < 0.05) of unconjugated norbuprenorphine but decreased its renal clearance (P < 0.001). Mild dizziness and nausea occurred during both study phases.

Conclusions

Voriconazole greatly increases exposure to oral buprenorphine, mainly by inhibiting intestinal and liver CYP3A4. Effect on some transporters may explain elevated norbuprenorphine concentrations. Although oral buprenorphine is not commonly used, this interaction may become relevant in patients receiving sublingual buprenorphine together with voriconazole or other CYP3A4 or transporter inhibitors.

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

Similar content being viewed by others

References

  1. Dum JE, Herz A (1981) In vivo receptor binding of the opiate partial agonist, buprenorphine, correlated with its agonistic and antagonistic actions. Br J Pharmacol 74:627–633

    Article  CAS  Google Scholar 

  2. Leander JD (1987) Buprenorphine has potent kappa opioid receptor antagonist activity. Neuropharmacology 26:1445–1147

    Article  CAS  Google Scholar 

  3. Mattick RP, Ali R, White JM, O’Brien S, Wolk S, Danz C (2003) Buprenorphine versus methadone maintenance therapy: a randomized double-blind trial with 405 opioid-dependent patients. Addiction 98:441–452

    Article  Google Scholar 

  4. Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE (1994) Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther 55:569–580

    Article  CAS  Google Scholar 

  5. Cone EJ, Gorodetzky CW, Yousefnejad D, Buchwald WF, Johnson RE (1984) The metabolism and excretion of buprenorphine in humans. Drug Metab Disp 12:577–581

    CAS  Google Scholar 

  6. Elkader A, Sproule B (2005) Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence. Clin Pharmacokinet 44:661–680

    Article  CAS  Google Scholar 

  7. Mendelson J, Upton RA, Everhart ET, Jacob P 3rd, Jones RT (1997a) Bioavailability of sublingual buprenorphine. J Clin Pharmacol 37:31–37

    Article  CAS  Google Scholar 

  8. Nath RP, Upton RA, Everhart ET, Cheung P, Shwonek P, Jones RT, Mendelson JE (1999) Buprenorphine pharmacokinetics: relative bioavailability of sublingual tablet and liquid formulations. J Clin Pharmacol 39:619–623

    Article  CAS  Google Scholar 

  9. McAleer SD, Mills RJ, Polack T, Hussain T, Rolan PE, Gibbs AD, Mullins FG, Hussein Z (2003) Pharmacokinetics of high-dose buprenorphine following single administration of sublingual tablet formulations in opioid naïve healthy male volunteers under a naltrexone block. Drug Alcohol Depend 72:75–83

    Article  CAS  Google Scholar 

  10. Ciraulo DA, Hitzemann RJ, Somoza E, Knapp CM, Rotrosen J, Sarid-Segal O, Ciraulo AM, Greenblatt DJ, Chiang CN (2006) Pharmacokinetics and pharmacodynamics of multiple sublingual buprenorphine tablets in dose-escalation trials. J Clin Pharmacol 46:179–192

    Article  CAS  Google Scholar 

  11. Bullingham RE, McQuay HJ, Moore A, Bennett MR (1980) Buprenorphine kinetics. Clin Pharmacol Ther 28:667–672

    Article  CAS  Google Scholar 

  12. Fihlman M, Hemmilä T, Hagelberg NM, Kuusniemi K, Backman JT, Laitila J, Laine K, Neuvonen PJ, Olkkola KT, Saari TI (2016) Voriconazole more likely than posaconazole increases plasma exposure to sublingual buprenorphine causing a risk of a clinically important interaction. Eur J Clin Pharmacol 72:1363–1371

    Article  CAS  Google Scholar 

  13. Kharasch ED, Hoffer C, Whittington D, Sheffels P (2003) Role of P-glycoprotein in the intestinal absorption and clinical effects of morphine. Clin Pharmacol Ther 74:543–554

    Article  CAS  Google Scholar 

  14. Drewe J, Ball HA, Beglinger C, Peng B, Kemmler A, Schächinger H, Haefeli WE (2000) Effect of P-glycoprotein modulation on the clinical pharmacokinetics and adverse effects of morphine. Br J Clin Pharmacol 50:237–246

    Article  CAS  Google Scholar 

  15. Dagenais C, Graff CL, Pollack GM (2004) Variable modulation of opioid brain uptake by P-glycoprotein in mice. Biochem Pharmacol 67:269–276

    Article  CAS  Google Scholar 

  16. Iribarne C, Picart D, Dréano Y, Bail JP, Berthou F (1997) Involvement of cytochrome P450 3A4 in N-dealkylation of buprenorphine in human liver microsomes. Life Sci 60:1953–1964

    Article  CAS  Google Scholar 

  17. Kobayashi K, Yamamoto T, Chiba K, Tani M, Shimada N, Ishizaki T, Kuroiwa Y (1998) Human buprenorphine N-dealkylation is catalyzed by cytochrome P450 3A4. Drug Metab Dispos 26:818–821

    CAS  PubMed  Google Scholar 

  18. Moody DE, Slawson MH, Strain EC, Laycock JD, Spanbauer AC, Foltz RL (2002) A liquid chromatographic-electrospray ionization-tandem mass spectrometric method for determination of buprenorphine, its metabolite, norbuprenorphine, and a coformulant, naloxone, that is suitable for in vivo and in vitro metabolism studies. Anal Biochem 306:31–39

    Article  CAS  Google Scholar 

  19. Picard N, Cresteil T, Djebli N, Marquet P (2005) In vitro metabolism study of buprenorphine: evidence for new metabolic pathways. Drug Metab Dispos 33:689–695

    Article  CAS  Google Scholar 

  20. Brown SM, Holtzman M, Kim T, Kharasch ED (2011) Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active. Anesthesiology 115:1251–1260

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Rouguieg K, Picard N, Sauvage FL, Gaulier JM, Marquet P (2010) Contribution of the different UDP-glucuronosyltransferase (UGT) isoforms to buprenorphine and norbuprenorphine metabolism and relationship with the main UGT polymorphisms in a bank of human liver microsomes. Drug Metab Dispos 38:40–45

    Article  CAS  Google Scholar 

  22. Cone EJ, Gorodetzky CW, Yousefnejad D, Darwin WD (1985) 63Ni electron-capture gas chromatographic assay for buprenorphine and metabolites in human urine and feces. J Chromatogr 337:291–300

    Article  CAS  Google Scholar 

  23. Brewster D, Humphrey MJ, Mcleavy MA (1981) Biliary excretion, metabolism and enterohepatic circulation of buprenorphine. Xenobiotica 11:189–196

    Article  CAS  Google Scholar 

  24. Kapil RP, Cipriano A, Michels GH, Perrino P, O’Keefe SA, Shet MS, Colucci SV, Noveck RJ, Harris SC (2012) Effect of ketoconazole on the pharmacokinetic profile of buprenorphine following administration of a once-weekly buprenorphine transdermal system. Clin Drug Investig 32:583–592

    CAS  PubMed  Google Scholar 

  25. McCance-Katz EF, Moody DE, Morse GD, Ma Q, DiFrancesco R, Friedland G, Pade P, Rainey PM (2007) Interaction between buprenorphine and atazanavir or atazanavir/ritonavir. Drug Alcohol Depend 91:269–278

    Article  CAS  Google Scholar 

  26. Murayama N, Imai N, Nakane T, Shimizu M, Yamazaki H (2007) Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes. Biochem Pharmacol 73:2020–2026

    Article  CAS  Google Scholar 

  27. Niwa T, Shiraga T, Takagi A (2005) Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes. Biol Pharm Bull 28:1805–1808

    Article  CAS  Google Scholar 

  28. Jeong S, Nguyen PD, Desta Z (2009) Comprehensive in vitro analysis of voriconazole inhibition of eight cytochrome P450 (CYP) enzymes: major effect on CYPs 2B6, 2C9, 2C19, and 3A. Antimicrob Agents Chemother 53:541–551

    Article  CAS  Google Scholar 

  29. Fudala PJ, Bridge TP, Herbert S, Williford WO, Chiang CN, Jones K, Collins J, Raisch D, Casadonte P, Goldsmith RJ, Ling W, Malkerneker U, McNicholas L, Renner J, Stine S, Tusel D, Buprenorphine/Naloxone Collaborative Study Group (2003) Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl JMed 349:949–958

    Article  CAS  Google Scholar 

  30. Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE (2000) A comparison of levomethadyl acetate, buprenorphine, and METH for opioid dependence. N Engl J Med 343:1290–1297

    Article  CAS  Google Scholar 

  31. Das NG, Das SK (2004) Development of mucoadhesive dosage forms of buprenorphine for sublingual drug delivery. Drug Deliv 11:89–95

    Article  CAS  Google Scholar 

  32. Hagelberg NM, Fihlman M, Hemmilä T, Backman JT, Laitila J, Neuvonen PJ, Laine K, Olkkola KT, Saari TI (2006) Rifampicin decreases exposure to sublingual buprenorphine in healthy subjects. Pharmacol Res Perspect 4(6):e00271

    Article  Google Scholar 

  33. Michna E, Ross EL, Hynes WL, Nedeljkovic SS, Soumekh S, Janfaza D, Palombi D, Jamison RN (2004) Predicting aberrant drug behavior in patients treated for chronic pain. J Pain Symptom Manag 28:250–258

    Article  Google Scholar 

  34. Chhun S, Rey E, Tran A, Lortholary O, Pons G, Jullien V (2007) Simultaneous quantification of voriconazole and posaconazole in human plasma by high-performance liquid chromatography with ultra-violet detection. J Chromatogr B, Analyt Technol Biomed Life Sci 852:223–228

    Article  CAS  Google Scholar 

  35. Gruber VA, Rainey PM, Moody DE, Morse GD, Ma Q, Prathikanti S, Pade PA, Alvanzo AA, McCance-Katz EF (2012) Interactions between buprenorphine and the protease inhibitors darunavir-ritonavir and fosamprenavir-ritonavir. Clin Infect Dis 54:414–423

    Article  CAS  Google Scholar 

  36. Hulskotte EG, Bruce RD, Feng HP, Webster LR, Xuan F, Lin WH, O'Mara E, Wagner JA, Butterton JR (2015) Pharmacokinetic interaction between HCV protease inhibitor boceprevir and methadone or buprenorphine in subjects on stable maintenance therapy. Eur J Clin Pharmacol 71:303–311

    Article  CAS  Google Scholar 

  37. Bruce RD, Altice FL, Moody DE, Morse GD, Andrews L, Lin SN, Fang WB, Ma Q, Friedland GH (2010) Pharmacokinetic interactions between buprenorphine/naloxone and once-daily lopinavir/ritonavir. J Acquir Immune Defic Syndr 54:511–514

    Article  CAS  Google Scholar 

  38. Moody DE, Liu F, Fang WB (2015) Azole antifungal inhibition of buprenorphine, methadone and oxycodone in vitro metabolism. J Anal Toxicol 39:374–386

    Article  CAS  Google Scholar 

  39. Frechen S, Junge L, Saari TI, Suleiman AA, Rokitta D, Neuvonen PJ, Olkkola KT, Fuhr UA (2013) Semiphysiological population pharmacokinetic model for dynamic inhibition of liver and gut wall cytochrome P450 3A by voriconazole. Clin Pharmacokinet 52:763–781

    Article  CAS  Google Scholar 

  40. Hynninen VV, Olkkola KT, Leino K, Lundgren S, Neuvonen PJ, Rane A, Valtonen M, Laine K (2007) Effect of voriconazole on the pharmacokinetics of diclofenac. Fundam Clin Pharmacol 21:651–656

    Article  CAS  Google Scholar 

  41. DuBuske LM (2005) The role of P-glycoprotein and organic anion-transporting polypeptides in drug interactions. Drug Saf 28:789–801

    Article  CAS  Google Scholar 

  42. Alhaddad H, Cisternino S, Declèves X, Tournier N, Schlatter J, Chiadmi F, Risède P, Smirnova M, Besengez C, Scherrmann JM, Baud FJ, Mégarbane B (2012) Respiratory toxicity of buprenorphine results from the blockage of P-glycoprotein-mediated efflux of norbuprenorphine at the blood-brain barrier in mice. Crit Care Med 40:3215–3223

    Article  CAS  Google Scholar 

  43. Soelberg CD, Brown RE Jr, Du Vivier D, Meyer JE, Ramachandran BK (2017) The US opioid crisis: current federal and state legal issues. Anesth Analg 125:1675–1681

    Article  Google Scholar 

  44. Saari TI, Laine K, Leino K, Valtonen M, Neuvonen PJ, Olkkola KT (2006) Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Clin Pharmacol Ther 79:362–370

    Article  CAS  Google Scholar 

  45. Hagelberg NM, Nieminen TH, Saari TI, Neuvonen M, Neuvonen PJ, Laine K, Olkkola KT (2009) Voriconazole drastically increases exposure to oral oxycodone. Eur J Clin Pharmacol 65:263–271

    Article  CAS  Google Scholar 

  46. Olkkola KT, Ahonen J, 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

    CAS  PubMed  Google Scholar 

  47. Kaukonen KM, Olkkola KT, Neuvonen PJ (1997) Itraconazole increases plasma concentrations of quinidine. Clin Pharmacol Ther 62:510–517

    Article  CAS  Google Scholar 

  48. Varhe A, Olkkola KT, Neuvonen PJ (1994) Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 56:601–607

    Article  CAS  Google Scholar 

  49. Backman JT, Kivistö KT, Olkkola KT, Neuvonen PJ (1998) The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin. Eur J Clin Pharmacol 5453–5458, 54, 53

    Article  CAS  Google Scholar 

  50. Granfors MT, Backman JT, Neuvonen M, Ahonen J, Neuvonen PJ (2004) Fluvoxamine drastically increases concentrations and effects of tizanidine: a potentially hazardous interaction. Clin Pharmacol Ther 75:331–341

    Article  CAS  Google Scholar 

  51. Saari TI, Grönlund J, Hagelberg NM, Neuvonen M, Laine K, Neuvonen PJ, Olkkola KT (2010) Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and orally administered oxycodone. Eur J Clin Pharmacol 66:387–397

    Article  CAS  Google Scholar 

  52. Huestis MA, Cone EJ, Pirnay SO, Umbricht A, Preston KL (2013) Intravenous buprenorphine and norbuprenorphine pharmacokinetics in humans. Drug Alcohol Depend 131:258–262

    Article  CAS  Google Scholar 

  53. Bai SA, Xiang Q, Finn A (2016) Evaluation of the pharmacokinetics of single- and multiple-dose buprenorphine buccal film in healthy volunteers. Clin Ther 38:358–369

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Mrs. Elina Kahra (medical laboratory technologist, Clinical Pharmacology, TYKSLAB, Hospital District of Southwest Finland, Turku, Finland) for her skillful technical assistance.

Author information

Authors and Affiliations

  1. Department of Anaesthesiology and Intensive Care, University of Turku, P.O. Box 52, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland

    Mari Fihlman, Nora M. Hagelberg & Teijo I. Saari

  2. Division of Perioperative Services, Intensive Care and Pain Medicine, Turku University Hospital, Turku, Finland

    Mari Fihlman, Tuija Hemmilä, Nora M. Hagelberg & Teijo I. Saari

  3. Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    Janne T. Backman, Jouko Laitila & Pertti J Neuvonen

  4. Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland

    Kari Laine

  5. Medbase Ltd., Turku, Finland

    Kari Laine

  6. Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    Klaus T. Olkkola

Authors
  1. Mari Fihlman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tuija Hemmilä
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nora M. Hagelberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Janne T. Backman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jouko Laitila
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kari Laine
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pertti J Neuvonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Klaus T. Olkkola
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Teijo I. Saari
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Mari Fihlman took care of the clinical phase of the study and data collection, participated in data analysis and statistical analysis, and wrote the manuscript. Klaus Olkkola and Kari Laine designed the study, wrote the protocol, supervised and coordinated the clinical implementation of the study, and participated in data analysis and manuscript preparation. Tuija Hemmilä participated the clinical phase and data collection. Janne T. Backman, Jouko Laitila, and Pertti J Neuvonen performed the analytical assays and participated in manuscript preparation. Teijo Saari analyzed the data, performed statistical analysis, and wrote the manuscript. All authors materially participated in the research and/or manuscript preparation. All authors have contributed to and approved the final manuscript.

Funding information

This study was supported financially by Turku University Hospital research fund (EVO 13821), Turku, Finland.

Corresponding author

Correspondence to Teijo I. Saari.

Ethics declarations

The study protocol was approved by the ethics committee of the Hospital District of Southwest Finland and by the Finnish National Agency for Medicines and was registered in the EudraCT clinical trials register under code 2011-001939-23.

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplemental Figure 1.

Individual pharmacokinetic parameters after oral buprenorphine. Values for maximum concentration (Cmax), area under plasma concentration–time curve (AUC0-18), elimination half-life (t½) and amount of urinary buprenorphine excreted during 18 h (Ae (0-18)) in 12 healthy subjects after 3.6 mg (placebo phase) or 0.2 mg (voriconazole phase) of oral buprenorphine on the fifth day of pretreatment with placebo or voriconazole 400 mg twice on day 1 and 200 mg twice on days 2-5. The horizontal line in the box represents the median, white diamonds show the mean, the box shows the interquartile range, and whiskers show the 10th and 90th percentiles. Values are normalized for an oral dose of 1.0 mg. (PNG 137 kb)

High resolution image (TIFF 139 kb)

Supplemental Figure 2.

Individual pharmacokinetic parameters of norbuprenorphine after oral buprenorphine. Values for maximum concentration (Cmax), area under plasma concentration–time curve (AUC0-18), amount of urinary norbuprenorphine excreted during 18 h (Ae(0-18)) and renal clearance (Clrenal) in 12 healthy subjects after 3.6 mg (placebo phase) or 0.2 mg (voriconazole phase) of oral buprenorphine on the fifth day of pretreatment with placebo or voriconazole 400 mg twice on day 1 and 200 mg twice on days 2-5. The horizontal line in the box represents the median, white diamonds show the mean, the box shows the interquartile range, and whiskers show the 10th and 90th percentiles. Values are normalized for an oral dose of 1.0 mg. (PNG 9110 kb)

High resolution image (TIFF 978 kb)

ESM 3

(PDF 95 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fihlman, M., Hemmilä, T., Hagelberg, N.M. et al. Voriconazole greatly increases the exposure to oral buprenorphine. Eur J Clin Pharmacol 74, 1615–1622 (2018). https://doi.org/10.1007/s00228-018-2548-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-018-2548-8

Keywords

Search

Navigation