Alimentary Pharmacology and Therapeutics Letters to the Editors be explained by the interaction on the CYP3A4 level. Further pharmacological studies should clarify the mechanism of this clinically highly relevant interaction.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Mullish BH, Kabir MS, Thursz MR, Dhar A. Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation. Aliment Pharmacol Ther 2014; 40: 880–92. 2. Sager JE, Lutz JD, Foti RS, Davis C, Kunze KL, Isoherranen N. Fluoxetine- and norfluoxetine-mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4. Clin Pharmacol Ther 2014; 95: 653–62.
Letter: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation – authors’ reply B. H. Mullish, M. S. Kabir, M. R. Thursz & A. Dhar Section of Hepatology, Faculty of Medicine, Imperial College London, London, UK. E-mail: [email protected] doi:10.1111/apt.13146
SIRS, We thank Chobanyan-J€ urgens et al. for their letter1 in response to our review.2 Their comments help to emphasise the important point about the many complexities that exist within this area, including both the rational design of pharmacokinetic studies, and of meaningful interpretations from them about clinically-relevant drug interactions. Whilst carefully designed studies have provided convincing evidence for both fluoxetine3 and paroxetine4 as being inhibitors of cytochrome P450 3A4 in vitro, we agree that the in vivo data published to date is contradictory5 but overall much less compelling. However, the pharmacokinetic studies performed so far in humans have a number of obvious limitations. For example, the two in vivo studies quoted by Chobanyan-J€ urgens 1, 6, 7 et al. used no more than 16 participants, all without comorbidities, in whom fluoxetine was administered for at most 12 days; this is a situation so far removed from that in which medical prescribers typically operate 914
3. DeVane CL, Donovan JL, Liston HL, et al. Comparative CYP3A4 inhibitory effects of venlafaxine, fluoxetine, sertraline, and nefazodone in healthy volunteers. J Clin Psychopharmacol 2004; 24: 4–10. 4. European Medicines Agency (EMA). Prozac- Article 6 (12) referral - Annex I, II, III (first published: 05/09/2006). http:// www.ema.europa.eu/docs/en_GB/document_library/ Referrals_document/Prozac_6_12/WC500013227.pdf (accessed 02 February 2015). 5. European Medicines Agency (EMA). Paroxetine - Article 31 referral - Annex I, II, III, IV (first published: 21/11/2005). http:// www.ema.europa.eu/docs/en_GB/document_library/ Referrals_document/Paroxetine_31/WC500012852.pdf (accessed 02 February 2015). 6. Drug Information System: AiDKlinik® Release 1.9.16 Revision 23502 - 2015 Dosing GmbH Heidelberg. 7. The evidence-based Drug Information System: MICROMEDEX® SOLUTIONS Truven Health Analytics Inc. 2015.
that its direct implications for drug interactions in clinical practice are of doubtful significance at best. However, we fully agree with Chobanyan-J€ urgens 1 et al. that more pharmacological studies within this area are urgently required. For such studies to be of relevance to clinicians, there is a major need for ‘real world’ patients with chronic liver disease or liver transplantation to be included. This need is more relevant now than ever before as pharmacological therapies within hepatology arrive and evolve, not least the recent explosion of novel oral anti-virals as treatment for chronic hepatitis C.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES 1. Chobanyan-J€ urgens K, Leiskau C, Sabau R, et al. Letter: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation. Aliment Pharmacol Ther 2015; 41: 913–4. 2. Mullish BH, Kabir MS, Thursz MR, et al. Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation. Aliment Pharmacol Ther 2014; 40: 880–92. 3. Lutz JD, VandenBrink BM, Babu KN, et al. Stereoselective inhibition of CYP2C19 and CYP3A4 by fluoxetine and its metabolite: implications for risk assessment of multiple timedependent inhibitor systems. Drug Metab Dispos 2013; 41: 2056–65. 4. Jornil J, Jensen KG, Larsen F, et al. Identification of cytochrome P450 isoforms involved in the metabolism of paroxetine and estimation of their importance for human paroxetine
Aliment Pharmacol Ther 2015; 41: 909–915 ª 2015 John Wiley & Sons Ltd
Letters to the Editors metabolism using a population-based simulator. Drug Metab Dispos 2010; 38: 376–85. 5. Grimsley SR, Jann MW, Carter JG, et al. Increased carbamazepine plasma concentrations after fluoxetine coadministration. Clin Pharmacol Ther 1991; 50: 10–5. 6. Sager JE, Lutz JD, Foti RS, et al. Fluoxetine and norfluoxetinemediated complex drug-drug interactions: in vitro to in vivo
Aliment Pharmacol Ther 2015; 41: 909–915 ª 2015 John Wiley & Sons Ltd
correlation of effects on CYP2D6, CYP2C19, and CYP3A4. Clin Pharmacol Ther 2014; 95: 653–62. 7. DeVane CL, Donovan JL, Liston HL, et al. Comparative CYP3A4 inhibitory effects of venlafaxine, fluoxetine, sertraline, and nefazodone in healthy volunteers. J Clin Psychopharmacol 2004; 24: 4–10.
915
Copyright of Alimentary Pharmacology & Therapeutics is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Mullish BH, Kabir MS, Thursz MR, Dhar A. Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation. Aliment Pharmacol Ther 2014; 40: 880–92. 2. Sager JE, Lutz JD, Foti RS, Davis C, Kunze KL, Isoherranen N. Fluoxetine- and norfluoxetine-mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4. Clin Pharmacol Ther 2014; 95: 653–62.
Letter: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation – authors’ reply B. H. Mullish, M. S. Kabir, M. R. Thursz & A. Dhar Section of Hepatology, Faculty of Medicine, Imperial College London, London, UK. E-mail: [email protected] doi:10.1111/apt.13146
SIRS, We thank Chobanyan-J€ urgens et al. for their letter1 in response to our review.2 Their comments help to emphasise the important point about the many complexities that exist within this area, including both the rational design of pharmacokinetic studies, and of meaningful interpretations from them about clinically-relevant drug interactions. Whilst carefully designed studies have provided convincing evidence for both fluoxetine3 and paroxetine4 as being inhibitors of cytochrome P450 3A4 in vitro, we agree that the in vivo data published to date is contradictory5 but overall much less compelling. However, the pharmacokinetic studies performed so far in humans have a number of obvious limitations. For example, the two in vivo studies quoted by Chobanyan-J€ urgens 1, 6, 7 et al. used no more than 16 participants, all without comorbidities, in whom fluoxetine was administered for at most 12 days; this is a situation so far removed from that in which medical prescribers typically operate 914
3. DeVane CL, Donovan JL, Liston HL, et al. Comparative CYP3A4 inhibitory effects of venlafaxine, fluoxetine, sertraline, and nefazodone in healthy volunteers. J Clin Psychopharmacol 2004; 24: 4–10. 4. European Medicines Agency (EMA). Prozac- Article 6 (12) referral - Annex I, II, III (first published: 05/09/2006). http:// www.ema.europa.eu/docs/en_GB/document_library/ Referrals_document/Prozac_6_12/WC500013227.pdf (accessed 02 February 2015). 5. European Medicines Agency (EMA). Paroxetine - Article 31 referral - Annex I, II, III, IV (first published: 21/11/2005). http:// www.ema.europa.eu/docs/en_GB/document_library/ Referrals_document/Paroxetine_31/WC500012852.pdf (accessed 02 February 2015). 6. Drug Information System: AiDKlinik® Release 1.9.16 Revision 23502 - 2015 Dosing GmbH Heidelberg. 7. The evidence-based Drug Information System: MICROMEDEX® SOLUTIONS Truven Health Analytics Inc. 2015.
that its direct implications for drug interactions in clinical practice are of doubtful significance at best. However, we fully agree with Chobanyan-J€ urgens 1 et al. that more pharmacological studies within this area are urgently required. For such studies to be of relevance to clinicians, there is a major need for ‘real world’ patients with chronic liver disease or liver transplantation to be included. This need is more relevant now than ever before as pharmacological therapies within hepatology arrive and evolve, not least the recent explosion of novel oral anti-virals as treatment for chronic hepatitis C.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES 1. Chobanyan-J€ urgens K, Leiskau C, Sabau R, et al. Letter: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation. Aliment Pharmacol Ther 2015; 41: 913–4. 2. Mullish BH, Kabir MS, Thursz MR, et al. Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation. Aliment Pharmacol Ther 2014; 40: 880–92. 3. Lutz JD, VandenBrink BM, Babu KN, et al. Stereoselective inhibition of CYP2C19 and CYP3A4 by fluoxetine and its metabolite: implications for risk assessment of multiple timedependent inhibitor systems. Drug Metab Dispos 2013; 41: 2056–65. 4. Jornil J, Jensen KG, Larsen F, et al. Identification of cytochrome P450 isoforms involved in the metabolism of paroxetine and estimation of their importance for human paroxetine
Aliment Pharmacol Ther 2015; 41: 909–915 ª 2015 John Wiley & Sons Ltd
Letters to the Editors metabolism using a population-based simulator. Drug Metab Dispos 2010; 38: 376–85. 5. Grimsley SR, Jann MW, Carter JG, et al. Increased carbamazepine plasma concentrations after fluoxetine coadministration. Clin Pharmacol Ther 1991; 50: 10–5. 6. Sager JE, Lutz JD, Foti RS, et al. Fluoxetine and norfluoxetinemediated complex drug-drug interactions: in vitro to in vivo
Aliment Pharmacol Ther 2015; 41: 909–915 ª 2015 John Wiley & Sons Ltd
correlation of effects on CYP2D6, CYP2C19, and CYP3A4. Clin Pharmacol Ther 2014; 95: 653–62. 7. DeVane CL, Donovan JL, Liston HL, et al. Comparative CYP3A4 inhibitory effects of venlafaxine, fluoxetine, sertraline, and nefazodone in healthy volunteers. J Clin Psychopharmacol 2004; 24: 4–10.
915
Copyright of Alimentary Pharmacology & Therapeutics is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
