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Effect of a Roux-en-Y Gastric Bypass on the Pharmacokinetics of Oral Morphine Using a Population Approach

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Abstract

Background and Objectives

Obesity and opioid use for chronic pain in obese individuals are both important public health concerns. The pharmacokinetics of oral morphine after Roux-en-Y gastric bypass (RYGB) are unknown. Therefore, we aimed to study the pharmacokinetics of oral morphine in morbidly obese patients before and after RYGB surgery, to identify the effects of RYGB and the subsequent reversal of morbid obesity on the pharmacokinetic parameters of morphine.

Methods

The pharmacokinetics of oral morphine (30 mg) were studied in 30 obese patients before (Visit 1) and then 7–15 days (Visit 2) and 6 months (Visit 3) after RYGB. A population pharmacokinetic model was used to describe the time course of the plasma morphine concentration, to study the effect of RYGB on morphine pharmacokinetics and to estimate inter-patient variability.

Results

The oral morphine time to maximum plasma concentration (t max) was twofold lower and maximum plasma concentration (C max) was 1.7 times higher at Visit 2, and t max was 7.5 times lower and C max 3.3 times higher at Visit 3 than at Visit 1. The mean oral morphine area under the plasma concentration–time curve (AUC) increased significantly (1.55-fold) between Visits 1 and 3. Changes in body mass index (BMI) after RYGB were clearly associated with decreased apparent oral morphine clearance and apparent central and peripheral morphine volumes of distribution. None of the other anthropometric parameters explained the inter-subject variability in morphine exposure better than BMI.

Conclusion

RYGB and the BMI reduction that followed it dramatically increased the rate of morphine absorption and slightly increased morphine exposure. The dose of immediate-release forms of morphine may be divided in obese patients after RYGB to prevent adverse events due to early and high morphine plasma peaks.

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References

  1. Obesity and overweight. WHO Fact Sheet no. 311. Available at URL:http://www.who.int/mediacentre/factsheets/fs311/en. Accessed 8 Aug 2014.

  2. American Society for Metabolic and Bariatric Surgery (ASMBS). Final report May 2011. Media Press Kit. Gainesville: American Society for Metabolic and Bariatric Surgery; 2011. http://s3.amazonaws.com/publicASMBS/MediaPressKit/MetabolicBariatricSurgeryOverviewJuly2011.pdf. Accessed 31 Jul 2014.

  3. Padwal R, Brocks D, Sharma AM. A systematic review of drug absorption following bariatric surgery and its theoretical implications. Obes Rev. 2010;11:41–50.

    Article  PubMed  CAS  Google Scholar 

  4. Padwal RS, Ben-Eltriki M, Wang X, Langkaas LA, Sharma AM, Birch DW, et al. Effect of gastric bypass surgery on azithromycin oral bioavailability. J Antimicrob Chemother. 2012;67:2203–6.

    Article  PubMed  CAS  Google Scholar 

  5. Padwal RS, Gabr RQ, Sharma AM, Langkaas LA, Birch DW, Karmali S, et al. Effect of gastric bypass surgery on the absorption and bioavailability of metformin. Diabetes Care. 2011;34:1295–300.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Hamad GG, Helsel JC, Perel JM, Kozak GM, McShea MC, Hughes C, et al. The effect of gastric bypass on the pharmacokinetics of serotonin reuptake inhibitors. Am J Psychiatry. 2012;169:256–63.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Roerig JL, Steffen K, Zimmerman C, Mitchell JE, Crosby RD, Cao L. Preliminary comparison of sertraline levels in postbariatric surgery patients versus matched nonsurgical cohort. Surg Obes Relat Dis. 2012;8:62–6.

    Article  PubMed  Google Scholar 

  8. Skottheim IB, Stormark K, Christensen H, Jakobsen GS, Hjelmesaeth J, Jenssen T, et al. Significantly altered systemic exposure to atorvastatin acid following gastric bypass surgery in morbidly obese patients. Clin Pharmacol Ther. 2009;86:311–8.

    Article  PubMed  CAS  Google Scholar 

  9. De Smet J, Colin P, De Paepe P, Ruige J, Batens H, Van Nieuwenhove Y, et al. Oral bioavailability of moxifloxacin after Roux-en-Y gastric bypass surgery. J Antimicrob Chemother. 2012;67:226–9.

    Article  PubMed  Google Scholar 

  10. Skottheim IB, Jakobsen GS, Stormark K, Christensen H, Hjelmesaeth J, Jenssen T, et al. Significant increase in systemic exposure of atorvastatin after biliopancreatic diversion with duodenal switch. Clin Pharmacol Ther. 2010;87:699–705.

    Article  PubMed  CAS  Google Scholar 

  11. Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet. 2010;49:71–87.

    Article  PubMed  CAS  Google Scholar 

  12. Brill MJ, Diepstraten J, van Rongen A, van Kralingen S, van den Anker JN, Knibbe CA. Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmacokinet. 2012;51:277–304.

    Article  PubMed  CAS  Google Scholar 

  13. Hooper MM, Stellato TA, Hallowell PT, Seitz BA, Moskowitz RW. Musculoskeletal findings in obese subjects before and after weight loss following bariatric surgery. Int J Obes (Lond). 2007;31:114–20.

    Article  CAS  Google Scholar 

  14. Raebel MA, Newcomer SR, Reifler LM, Boudreau D, Elliott TE, DeBar L, et al. Chronic use of opioid medications before and after bariatric surgery. JAMA. 2013;310:1369–76.

    Article  PubMed  CAS  Google Scholar 

  15. Lloret Linares C, Hajj A, Poitou C, Simoneau G, Clement K, Laplanche JL, et al. Pilot study examining the frequency of several gene polymorphisms involved in morphine pharmacodynamics and pharmacokinetics in a morbidly obese population. Obes Surg. 2011;21:1257–64.

    Article  PubMed  Google Scholar 

  16. Lloret Linares C, Decleves X, Oppert JM, Basdevant A, Clement K, Bardin C, et al. Pharmacology of morphine in obese patients: clinical implications. Clin Pharmacokinet. 2009;48:635–51.

    Article  PubMed  Google Scholar 

  17. Hitt HC, McMillen RC, Thornton-Neaves T, Koch K, Cosby AG. Comorbidity of obesity and pain in a general population: results from the Southern Pain Prevalence Study. J Pain. 2007;8:430–6.

    Article  PubMed  Google Scholar 

  18. Sjostrom L, Narbro K, Sjostrom CD, Karason K, Larsson B, Wedel H, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007;357:741–52.

    Article  PubMed  Google Scholar 

  19. Lloret Linares C, Ciangura C, Bouillot JL, Coupaye M, Decleves X, Poitou C, et al. Validity of leg-to-leg bioelectrical impedance analysis to estimate body fat in obesity. Obes Surg. 2011;21:917–23.

    Article  PubMed  Google Scholar 

  20. Boddy K, King PC, Hume R, Weyers E. The relation of total body potassium to height, weight, and age in normal adults. J Clin Pathol. 1972;25:512–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B. Quantification of lean bodyweight. Clin Pharmacokinet. 2005;44:1051–65.

    Article  PubMed  Google Scholar 

  22. Devine BJ. Gentamicin therapy. Drug Intell Clin Pharm. 1974;8:650–5.

  23. Hull JH, Sarubbi FA Jr. Gentamicin serum concentrations: pharmacokinetic predictions. Ann Intern Med. 1976;85:183–9.

    Article  PubMed  CAS  Google Scholar 

  24. Suter M, Giusti V, Heraief E, Zysset F, Calmes JM. Laparoscopic Roux-en-Y gastric bypass: initial 2-year experience. Surg Endosc. 2003;17:603–9.

    Article  PubMed  CAS  Google Scholar 

  25. Dodet P, Perrot S, Auvergne L, Hajj A, Simoneau G, Decleves X, et al. Sensory impairment in obese patients? sensitivity and pain detection thresholds for electrical stimulation after surgery-induced weight loss, and comparison with a nonobese population. Clin J Pain. 2013;29:43–9.

    Article  PubMed  Google Scholar 

  26. Chast F, Bardin C, Sauvageon-Martre H, Callaert S, Chaumeil JC. Systemic morphine pharmacokinetics after ocular administration. J Pharm Sci. 1991;80:911–7.

    Article  PubMed  CAS  Google Scholar 

  27. Hirt D, Urien S, Ekouevi DK, Rey E, Arrive E, Blanche S, et al. Population pharmacokinetics of tenofovir in HIV-1-infected pregnant women and their neonates (ANRS 12109). Clin Pharmacol Ther. 2009;85:182–9.

    Article  PubMed  CAS  Google Scholar 

  28. Staahl C, Upton R, Foster DJ, Christrup LL, Kristensen K, Hansen SH, et al. Pharmacokinetic-pharmacodynamic modeling of morphine and oxycodone concentrations and analgesic effect in a multimodal experimental pain model. J Clin Pharmacol. 2008;48:619–31.

    Article  PubMed  CAS  Google Scholar 

  29. Lotsch J, Weiss M, Ahne G, Kobal G, Geisslinger G. Pharmacokinetic modeling of M6G formation after oral administration of morphine in healthy volunteers. Anesthesiology. 1999;90:1026–38.

    Article  PubMed  CAS  Google Scholar 

  30. Dirksen C, Damgaard M, Bojsen-Moller KN, Jorgensen NB, Kielgast U, Jacobsen SH, et al. Fast pouch emptying, delayed small intestinal transit, and exaggerated gut hormone responses after Roux-en-Y gastric bypass. Neurogastroenterol Motil. 2013;25:346-e255.

    Article  PubMed  Google Scholar 

  31. Steffen KJ, Engel SG, Pollert GA, Li C, Mitchell JE. Blood alcohol concentrations rise rapidly and dramatically after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2013;9:470–3.

    Article  PubMed  Google Scholar 

  32. Hasselstrom J, Sawe J. Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations. Clin Pharmacokinet. 1993;24:344–54.

    Article  PubMed  CAS  Google Scholar 

  33. Kharasch ED, Hoffer C, Whittington D, Sheffels P. Role of P-glycoprotein in the intestinal absorption and clinical effects of morphine. Clin Pharmacol Ther. 2003;74:543–54.

    Article  PubMed  CAS  Google Scholar 

  34. Xu J, Kulkarni SR, Li L, Slitt AL. UDP-glucuronosyltransferase expression in mouse liver is increased in obesity- and fasting-induced steatosis. Drug Metab Dispos. 2012;40:259–66.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Congiu M, Mashford ML, Slavin JL, Desmond PV. UDP glucuronosyltransferase mRNA levels in human liver disease. Drug Metab Dispos. 2002;30:129–34.

    Article  PubMed  CAS  Google Scholar 

  36. Lumeng CN, Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest. 2011;121:2111–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Tchernof A, Levesque E, Beaulieu M, Couture P, Despres JP, Hum DW, et al. Expression of the androgen metabolizing enzyme UGT2B15 in adipose tissue and relative expression measurement using a competitive RT-PCR method. Clin Endocrinol (Oxf). 1999;50:637–42.

    Article  CAS  Google Scholar 

  38. Ziccardi P, Nappo F, Giugliano G, Esposito K, Marfella R, Cioffi M, et al. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation. 2002;105:804–9.

    Article  PubMed  CAS  Google Scholar 

  39. van Kralingen S, Taks M, Diepstraten J, van de Garde EM, van Dongen EP, Wiezer MJ, et al. Pharmacokinetics and protein binding of cefazolin in morbidly obese patients. Eur J Clin Pharmacol. 2011;67:985–92.

    Article  PubMed  CAS  Google Scholar 

  40. Sparreboom A, Wolff AC, Mathijssen RH, Chatelut E, Rowinsky EK, Verweij J, et al. Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese. J Clin Oncol. 2007;25:4707–13.

    Article  PubMed  CAS  Google Scholar 

  41. Pai MP, Bearden DT. Antimicrobial dosing considerations in obese adult patients. Pharmacotherapy. 2007;27:1081–91.

    Article  PubMed  CAS  Google Scholar 

  42. Green B, Duffull SB. What is the best size descriptor to use for pharmacokinetic studies in the obese? Br J Clin Pharmacol. 2004;58:119–33.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Chatelut E, Puisset F. The scientific basis of body surface area-based dosing. Clin Pharmacol Ther. 2014;95:359–61.

    Article  PubMed  CAS  Google Scholar 

  44. Drake J, Kirkpatrick CT, Aliyar CA, Crawford FE, Gibson P, Horth CE. Effect of food on the comparative pharmacokinetics of modified-release morphine tablet formulations: oramorph SR and MST Continus. Br J Clin Pharmacol. 1996;41:417–20.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  45. Hasselstrom J, Alexander N, Bringel C, Svensson JO, Sawe J. Single-dose and steady-state kinetics of morphine and its metabolites in cancer patients—a comparison of two oral formulations. Eur J Clin Pharmacol. 1991;40:585–91.

    PubMed  CAS  Google Scholar 

  46. Osborne R, Joel S, Trew D, Slevin M. Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Clin Pharmacol Ther. 1990;47:12–9.

    Article  PubMed  CAS  Google Scholar 

  47. Lotsch J, Zimmermann M, Darimont J, Marx C, Dudziak R, Skarke C, Geisslinger G. Does the A118G polymorphism at the mu-opioid receptor gene protect against morphine-6-glucuronide toxicity? Anesthesiology. 2002;97:814–9.

    Article  PubMed  Google Scholar 

  48. Skarke C, Darimont J, Schmidt H, Geisslinger G, Lotsch J. Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin Pharmacol Ther. 2003;73:107–21.

    Article  PubMed  CAS  Google Scholar 

  49. Shibutani K, Inchiosa MA Jr, Sawada K, Bairamian M. Accuracy of pharmacokinetic models for predicting plasma fentanyl concentrations in lean and obese surgical patients: derivation of dosing weight (“pharmacokinetic mass”). Anesthesiology. 2004;101:603–13.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Juliette Oliary and Guy Simoneau for help throughout the study. The English text was edited by Dr Owen Parkes. This study was funded in part by the Société d’Evaluation et de Traitement de la Douleur (SFETD-France) and the Groupe Pasteur Mutualité.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Inserm, UMR-S 1144 Université Paris Descartes-Paris Diderot, Variabilité de réponse aux psychotropes, Paris, France

    Célia Lloret-Linares, Stéphane Mouly, Jean-Michel Scherrmann, Jean-François Bergmann & Xavier Declèves

  2. Therapeutic Research Unit, Department of Internal Medicine, Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Paris, France

    Célia Lloret-Linares, Stéphane Mouly & Jean-François Bergmann

  3. Clinical Pharmacology Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France

    Déborah Hirt

  4. Clinical Pharmacy Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France

    Christophe Bardin & François Chast

  5. Pharmacokinetics and Pharmacochemistry Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France

    Christophe Bardin & Xavier Declèves

  6. Department of Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Ambroise Paré, Université Versailles Saint Quentin, Boulogne, France

    Jean-Luc Bouillot

  7. Human Nutrition Research Center, INSERM U755, Hôpital La Pitié-Salpétrière, Paris, France

    Jean-Michel Oppert & Christine Poitou

  8. Hôpital Lariboisière-Service de Médecine Interne A, 2 rue Ambroise Paré, 75010, Paris, France

    Célia Lloret-Linares

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  1. Célia Lloret-Linares
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  2. Déborah Hirt
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  3. Christophe Bardin
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  7. François Chast
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Corresponding author

Correspondence to Célia Lloret-Linares.

Additional information

C. Lloret-Linares and D. Hirt contributed equally to the work.

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Supplemental Figure. Means and Standard Deviations of observed plasma morphine concentrations versus time before surgery (Visit 1), 8-15 days after surgery (Visit 2), and 6 months after surgery (Visit 3)

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Lloret-Linares, C., Hirt, D., Bardin, C. et al. Effect of a Roux-en-Y Gastric Bypass on the Pharmacokinetics of Oral Morphine Using a Population Approach. Clin Pharmacokinet 53, 919–930 (2014). https://doi.org/10.1007/s40262-014-0163-0

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