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Morphine Metabolite Pharmacokinetics during Venoarterial Extra Corporeal Membrane Oxygenation in Neonates

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Abstract

Objective

To examine morphine metabolite serum concentrations in neonates undergoing venoarterial extra corporeal membrane oxygenation (ECMO) and to quantify clearance differences between these neonates and those subjected to noncardiac major surgery.

Patients and methods

This was an observational study in level III referral centre. Fourteen neonates (<7 days old) undergoing ECMO were included. Morphine and concomitant medications were given by protocol, adapted to the clinical conditions of the neonates. Pharmacokinetic findings were compared with those from a previous study in infants after noncardiac major surgery. Nonlinear mixed-effect modelling was used. Parameter estimates were standardised to a 70kg person using allometric modeling

Results

Morphine-3-glucuronide (M3G) was the predominant metabolite. Formation clearance to M3G at the start of ECMO on day 1 was lower than those in postoperative children, but matured more rapidly. After 10 days formation clearances of M3G in neonates on ECMO equalled those of postoperative children. Higher ECMO flows were associated with reduced formation clearances. Elimination clearances of M3G, but not morphine-6-glucuronide (M6G), were lower in the ECMO neonates; this was attributable to reduced renal clearance. These elimination clearances were correlated positively with ECMO flow and negatively with dopamine dose. Haemofiltration cleared M3G and M6G, but not morphine.

Conclusion

Formation clearance to M3G, the predominant metabolite, is reduced during the first 10 days of ECMO. Elimination clearance of M3G and M6G is related to creatinine clearance. ECMO flow had a small effect on metabolite clearance. Higher flows were associated with decreased formation clearances, possibly reflecting illness severity. Dopamine dose reflected decreased renal clearance.

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References

  1. Iyer LV, Ho MN, Shinn WM, et al. Glucuronidation of 1′-hydroxyestragole (1′-HE) by human UDP-glucuronosyltrans-ferases UGT2B7 and UGT1A9. Toxicol Sci 2003; 73: 36–43

    Article  PubMed  CAS  Google Scholar 

  2. Green MD, King CD, Mojarrabi B, et al. Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3. Drug Metab Dispos 1998; 26: 507–12

    PubMed  CAS  Google Scholar 

  3. Frances B, Gout R, Monsarrat B, et al. Further evidence that morphine-6 beta-glucuronide is a more potent opioid agonist than morphine. J Pharmacol Exp Ther 1992; 262: 25–31

    PubMed  CAS  Google Scholar 

  4. Paul D, Standifer KM, Inturrisi CE, et al. Pharmacological characterization of morphine-6 beta-glucuronide, a very potent morphine metabolite. J Pharmacol Exp Ther 1989; 251: 477–83

    PubMed  CAS  Google Scholar 

  5. Smith MT, Watt JA, Cramond T. Morphine-3-glucuronide: a potent antagonist of morphine analgesia. Life Sci 1990; 47: 579–85

    Article  PubMed  CAS  Google Scholar 

  6. Labella FS, Pinsky C, Havlicek V. Morphine derivatives with diminished opiate receptor potency show enhanced central excitatory activity. Brain Res 1979; 174: 263–71

    Article  PubMed  CAS  Google Scholar 

  7. Snead III OC. Opiate-induced seizures: a study of mu and delta specific mechanisms. Exp Neurol 1986; 93: 348–58

    Article  PubMed  CAS  Google Scholar 

  8. Woolf CJ. Intrathecal high dose morphine produces hyperalgesia in the rat. Brain Res 1981; 209: 491–5

    Article  PubMed  CAS  Google Scholar 

  9. Yaksh TL, Harty GJ, Onofrio BM. High dose of spinal morphine produce a nonopiate receptor-mediated hyperesthesia: clinical and theoretic implications. Anesthesiology 1986; 64: 590–7

    Article  PubMed  CAS  Google Scholar 

  10. Shohami E, Evron S, Weinstock M, et al. A new animal model for action myoclonus. Adv Neurol 1986; 43: 545–52

    PubMed  CAS  Google Scholar 

  11. Christrup LL. Morphine metabolites. Acta Anaesthesiol Scand 1997; 41: 116–22

    Article  PubMed  CAS  Google Scholar 

  12. Dagan O, Klein J, Gruenwald C, et al. Preliminary studies of the effects of extracorporeal membrane oxygenator on the disposition of common pediatrie drugs. Ther Drug Monit 1993; 15: 263–6

    Article  PubMed  CAS  Google Scholar 

  13. Dagan O, Klein J, Bohn D, et al. Effects of extracorporeal membrane oxygenation on morphine pharmacokinetics in infants. Crit Care Med 1994; 22: 1099–101

    Article  PubMed  CAS  Google Scholar 

  14. Peters JWB, Anderson BJ, Simons SHP, et al. Morphine Pharmacokinetics during venoarterial extracorporeal membrane oxygenation in neonates. Intensive Care Med 2005; 31: 257–63

    Article  PubMed  Google Scholar 

  15. Bouwmeester J, Andersen B, Tibboel D, et al. Developmental pharmacokinetics of morphine and metabolites in neonates, infants, and children. Br J Anaesth 2004; 92: 208–17

    Article  PubMed  CAS  Google Scholar 

  16. Anderson B. Disentangling PK-PD in neonates. Arch Dis Child Fetal Neonatal Ed 2004; 89: F3–4

    Article  PubMed  CAS  Google Scholar 

  17. Penson RT, Joel SP, Clark S, et al. Limited phase I study of morphine-3-glucuronide. J Pharm Sci 2001; 90: 1810–6

    Article  PubMed  CAS  Google Scholar 

  18. Hanna MH, Peat SJ, Knibb AA, et al. Disposition of morphine-6-glucuronide and morphine in healthy volunteers. Br J Anaesth 1991; 66: 103–7

    Article  PubMed  CAS  Google Scholar 

  19. Holford NHG. A size standard for pharmacokinetics. Clin Pharmacokinet 1996; 30: 329–32

    Article  PubMed  CAS  Google Scholar 

  20. Verwey-van Wissen CP, Koopman-Kimenai PM, Vree TB. Direct determination of codeine, norcodeine, morphine and normorphine with their corresponding O-glucuronide conjugates by high-performance liquid chromatography with electrochemical detection. J Chromotogr 1991; 570: 309–20

    Article  CAS  Google Scholar 

  21. West GB, Brown JH, Enquist BJ. A general model for the origin of allometric scaling laws in biology. Science 1997; 276: 122–6

    Article  PubMed  CAS  Google Scholar 

  22. Peters HP. Chpt 4. Physiological correlates of size. In: Beck E, Birks HJB, Conner EF, editors. The ecological implications of body size. Cambridge: Cambridge University Press, 1983: 48–53

    Chapter  Google Scholar 

  23. Karalis V, Macheras P. Drug disposition viewed in terms of the fractal volume of distribution. Pharm Res 2002; 19: 696–703

    PubMed  CAS  Google Scholar 

  24. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41

    Article  PubMed  CAS  Google Scholar 

  25. Berkenstadt H, Segal E, Mayan H, et al. The pharmacokinetics of morphine and lidocaine in critically ill patients. Intensive Care Med 1999; 25: 110–2

    Article  PubMed  CAS  Google Scholar 

  26. Lynn A, Nespeca MK, Bratton SL, et al. Clearance of morphine in postoperative infants during intravenous infusion: the influence of age and surgery. Anesth Analg 1998; 86: 958–63

    PubMed  CAS  Google Scholar 

  27. Pokela ML, Olkkola KT, Seppala T, et al. Age-related morphine kinetics in infants. Dev Pharmacol Ther 1993; 20: 26–34

    PubMed  CAS  Google Scholar 

  28. Dagan O, Klein J, Bohn D, et al. Morphine pharmacokinetics in children following cardiac surgery: effects of disease and inotropic support. J Cardiothorac Vase Anesth 1993; 7: 396–8

    Article  CAS  Google Scholar 

  29. 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 

  30. Van Crugten JT, Sallustio BC, Nation RL, et al. Renal tubular transport of morphine, morphine-6-glucuronide, and morphine-3-glucuronide in the isolated perfused rat kidney. Drug Metab Dispos 1991; 19: 1087–92

    PubMed  Google Scholar 

  31. Bjornsson TD. Use of serum creatinine concentrations to determine renal function. Clin Pharmacokinet 1979; 4: 200–22

    Article  PubMed  CAS  Google Scholar 

  32. Lynn AM, Nespeca MK, Bratton SL, et al. Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions. Pain 2000; 88: 89–95

    Article  PubMed  CAS  Google Scholar 

  33. McRorie TI, Lynn AM, Nespeca M, et al. The maturation of morphine clearance and metabolism. Am J Dis Child 1992; 146: 972–6

    PubMed  CAS  Google Scholar 

  34. de Wildt SN, Kearns GL, Leeder JS, et al. Glucuronidation in humans: pharmacogenetic and developmental aspects. Clin Pharmacokinet 1999; 36: 439–52

    Article  PubMed  Google Scholar 

  35. Oda Y, Mizutani K, Hase I, et al. Fentanyl inhibits metabolism of midazolam: competitive inhibition of CYP3A4 in vitro. Br J Anaesth 1999; 82: 900–3

    Article  PubMed  CAS  Google Scholar 

  36. Geiduschek JM, Lynn AM, Bratton SL, et al. Morphine pharmacokinetics during continuous infusion of morphine sulfate for infants receiving extracorporeal membrane oxygenation. Crit Care Med 1997; 25: 360–4

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors have no financial or other potential conflicts of interest that are relevant to the contents of this paper.

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Authors and Affiliations

  1. Department of Pediatric Surgery, Erasmus MC-Sophia, sp3404, PO Box 2060, Rotterdam, 3000 CB, The Netherlands

    Jemen W. B. Peters, Sinno H. P. Simons & Dick Tibboel

  2. Department of Pediatric Anesthesia, Erasmus MC-Sophia, Rotterdam, The Netherlands

    Jemen W. B. Peters

  3. Department of Anesthesiology, University of Auckland, Auckland, New Zealand

    Brian J. Anderson

  4. Department of Pharmacy and Toxicology, University Medical Center Groningen, Groningen, The Netherlands

    Donald R. A. Uges

Authors
  1. Jemen W. B. Peters
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  2. Brian J. Anderson
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  3. Sinno H. P. Simons
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  4. Donald R. A. Uges
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  5. Dick Tibboel
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Corresponding author

Correspondence to Jemen W. B. Peters.

Appendix

Appendix

The equations used in the final model were: Equation 8:

$${{\rm{V}}_{{\rm{Mecmo}}}}({\rm{L}}/70{\rm{kg}}) = {\rm{FV}} \bullet {{\rm{V}}_{{\rm{std}}}} \bullet ({\rm{W}}/70) \bullet \left\{ {1 - {\rm{\beta V}} \bullet {\rm{exp}}( - {\rm{PNA}}[{\rm{days}}] \bullet {\rm{Ln}}[2]/{\rm{TV}}} \right\})$$
((Eq. 8))

Equation 9:

$${\rm{FR}}{{\rm{F}}_{{\rm{ecmo}}}}({\rm{L}}/{\rm{h}}/70{\rm{kg}}) = 85.947/{\rm{creatinine}} \bullet {\rm{exp}}({\rm{Kage}} \bullet {\rm{PNA}}[{\rm{days}}]/365/40) \bullet {\rm{exp}}({\rm{Fflow}} \bullet {\rm{Flow}}) \bullet {\rm{exp}}({\rm{Fdop}} \bullet {\rm{dop}})$$
((Eq. 9))

Equation 10:

$${\rm{C}}{{\rm{L}}_{{\rm{fM}}3{\rm{Gecmo}}}}({\rm{L}}/{\rm{h}}/70{\rm{kg}}) = {\rm{C}}{{\rm{L}}_{{\rm{fM}}3{\rm{Gstd}}}} \bullet {({\rm{W}}/70)^{3/4}} \bullet (1 - {\rm{\beta C}}{{\rm{L}}_{\rm{f}}} \bullet {\rm{FCL}}03) \bullet {\rm{exp}}( - {\rm{PNA}}[{\rm{days}}] \bullet {\rm{Ln}}[2])/({\rm{TC}}{{\rm{L}}_{\rm{f}}} \bullet {\rm{FTCL}}3) \bullet {\rm{exp}}({\rm{Flow}} \bullet {\rm{Fpump}})$$
((Eq. 10))

where FCL03 is the base maturation CLfM3G and FTCL3 is the CLfM3G maturation half-life. Equation 11:

$${\rm{C}}{{\rm{L}}_{{\rm{fM}}6{\rm{Gecmo}}}}({\rm{L}}/{\rm{h}}/70{\rm{kg}}) = {\rm{C}}{{\rm{L}}_{{\rm{fM}}6{\rm{Gstd}}}} \bullet {({\rm{W}}/70)^{3/4}} \bullet (1 - {\rm{\beta C}}{{\rm{L}}_{\rm{f}}} \bullet {\rm{FCL}}06) \bullet {\rm{exp}}( - {\rm{PNA}}[{\rm{days}}] \bullet {\rm{Ln}}[2])/({\rm{TC}}{{\rm{L}}_{\rm{f}}} \bullet {\rm{FTCL}}6) \bullet {\rm{exp}}({\rm{Flow}} \bullet {\rm{Fpump}})$$
((Eq. 11))

where FCL06 is the base maturation CLfM6G and FTCL6 is the CLfM6G maturation half-life. Equation 12:

$${\rm{C}}{{\rm{L}}_{{\rm{M}}3{\rm{Gecmo}}}}({\rm{L}}/{\rm{h}}/70{\rm{kg}}) = {\rm{C}}{{\rm{L}}_{{\rm{M}}3{\rm{Gstd}}}} \bullet {({\rm{W}}/70)^{3/4}} \bullet (1 - {\rm{\beta CL}} \bullet {\rm{exp}}\{ - {\rm{PNA}}[{\rm{days}}] \bullet {\rm{Ln}}[2]/{\rm{TCL}}\} ) \bullet {\rm{FR}}{{\rm{F}}_{{\rm{ecmo}}}}$$
((Eq. 12))

Equation 13:

$${\rm{C}}{{\rm{L}}_{{\rm{M}}6{\rm{Gecmo}}}}({\rm{L}}/{\rm{h}}/70{\rm{kg}}) = {\rm{C}}{{\rm{L}}_{{\rm{M}}6{\rm{Gstd}}}} \bullet {({\rm{W}}/70)^{3/4}} \bullet (1 - {\rm{\beta CL}} \bullet {\rm{exp}}\{ - {\rm{PNA}}[{\rm{days}}] \bullet {\rm{Ln}}[2]/{\rm{TCL}}\} ) \bullet {\rm{FR}}{{\rm{F}}_{{\rm{ecmo}}}}$$
((Eq. 13))

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Peters, J.W.B., Anderson, B.J., Simons, S.H.P. et al. Morphine Metabolite Pharmacokinetics during Venoarterial Extra Corporeal Membrane Oxygenation in Neonates. Clin Pharmacokinet 45, 705–714 (2006). https://doi.org/10.2165/00003088-200645070-00005

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