1 Department of Anaesthesiology and 2 Paediatric Surgery, Sophia Childrens Hospital, University Hospital Rotterdam, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands. 3 Department of Anaesthesiology and 4 Pharmacology and Clinical Pharmacology, University of Auckland, New Zealand
*Corresponding author: c/o PICU, Auckland Childrens Hospital, Auckland, New Zealand. E-mail: briana@adhb.govt.nz
Accepted for publication: July 7, 2003
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. Postoperative children 03 yr old were given an intravenous loading dose of morphine hydrochloride (100 µg kg1 in 2 min) followed by either an intravenous morphine infusion of 10 µg h1 kg1 (n=92) or 3-hourly intravenous morphine boluses of 30 µg kg1 (n=92). Additional morphine (5 µg kg1) every 10 min was given if the visual analogue (VAS, 010) pain score was 4. Arterial blood (1.4 ml) was sampled within 5 min of the loading dose and at 6, 12 and 24 h for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The disposition of morphine and formation clearances of morphine base to its glucuronide metabolites and their elimination clearances were estimated using non-linear mixed effects models.
Results. The analysis used 1856 concentration observations from 184 subjects. Population parameter estimates and their variability (%) for a one-compartment, first-order elimination model were as follows: volume of distribution 136 (59.3) litres, formation clearance to M3G 64.3 (58.8) litres h1, formation clearance to M6G 3.63 (82.2) litres h1, morphine clearance by other routes 3.12 litres h1 per 70 kg, elimination clearance of M3G 17.4 (43.0) litres h1, elimination clearance of M6G 5.8 (73.8) litres h1. All parameters are standardized to a 70 kg person using allometric 3/4 power models and reflect fully mature adult values. The volume of distribution increased exponentially with a maturation half-life of 26 days from 83 litres per 70 kg at birth; formation clearance to M3G and M6G increased with a maturation half-life of 88.3 days from 10.8 and 0.61 litres h1 per 70 kg respectively at birth. Metabolite formation decreased with increased serum bilirubin concentration. Metabolite clearance increased with age (maturation half-life 129 days), and appeared to be similar to that described for glomerular filtration rate maturation in infants.
Conclusion. M3G is the predominant metabolite of morphine in young children and total body morphine clearance is 80% that of adult values by 6 months. A mean steady-state serum concentration of 10 ng ml1 can be achieved in children after non-cardiac surgery in an intensive care unit with a morphine hydrochloride infusion of 5 µg h1 kg1 at birth (term neonates), 8.5 µg h1 kg1 at 1 month, 13.5 µg h1 kg1 at 3 months and 18 µg h1 kg1 at 1 year and 16 µg h1 kg1 for 1- to 3-yr-old children.
Br J Anaesth 2004; 92: 20817
Keywords: anaesthesia, paediatric; analgesics opioid, morphine; metabolism, morphine metabolites; pharmacokinetics; pharmacometrics
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We had the opportunity to examine morphine and metabolite serum concentrations in children 03 yr old given either intermittent boluses or morphine infusion.9 10 These data have previously been analysed using multiple regression to investigate the effect of clinical variables, such as gestational age, sex, weight, the therapeutic regimens used and mechanical ventilation, on morphine requirements and plasma concentrations.10 That analysis revealed that age was the most important factor affecting morphine requirements and plasma morphine concentrations. Significantly fewer neonates required additional morphine doses compared with all other age groups and neonates had significantly higher plasma concentrations of morphine.10
This study analysis further investigated and quantified the effect of age using a population-based approach that included size as the primary covariate in an effort to disentangle age-related factors from size-related factors. Age-related morphine metabolite pharmacokinetics in children have not been quantified previously.
![]() |
Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
At the end of surgery, mechanical ventilation was continued in patients who required ventilator assistance after surgery. Directly after surgery, all patients were given an intravenous loading dose of morphine hydrochloride (100 µg kg1 over 2 min), followed by either an infusion of 10 µg h1 kg1 combined with 3-hourly intravenous placebo (saline) boluses over 2 min or a continuous placebo infusion (saline) combined with 3-hourly intravenous morphine hydrochloride boluses of 30 µg kg1. Additional morphine (5 µg kg1 every 10 min) was given if the visual analogue scale (VAS, 010) pain scores were 4. No other analgesic or sedative drugs were used.
Arterial blood samples (1.4 ml) were taken after induction of anaesthesia (baseline), at the end of surgery, and 6, 12 and 24 h after surgery to determine serum concentrations of morphine, M3G and M6G.
Pain was assessed 3-hourly by nurses trained in the use of the behavioural part of the COMFORT score11 and VAS (010). The VAS score was measured after the 2 min of observation needed for the COMFORT score.1114 Nursing interventions included pain assessment, blood sampling and administration of intermittent bolus (placebo or morphine) medication.
Morphine and metabolite assay
Serum aliquots (0.6 ml) were extracted with the Baker-10 extraction system (Baker Chemicals, Deventer, The Netherlands) fitted with 1-ml disposable cyclohexyl cartridges (C6H6, Baker, catalogue no. 7212-01). The extraction column was conditioned with two column volumes of methanol, two column volumes of water and 1 ml of 500 mM diammonium sulphate (pH=9.3). The serum (0.6 ml) was diluted with 0.6 ml 500 mM diammonium sulphate (pH=9.3) and washed with 2 ml of 50 mM diammonium sulphate (pH=9.3) after which it was allowed to dry for 15 s. The elution was carried out with 0.5 ml 0.01 M KH2PO4 buffer, pH=2.1, containing 11% acetonitrile. From this eluate, 50 µl was injected on the analytical column. The HPLC system comprised a Spectroflow 400 solvent delivery system (Kratos, Rotterdam, The Netherlands) equipped with a degasser (Separations, HI-Ambacht, The Netherlands), a Marathon auto sampler (Separations), a Spectroflow 773 UV detector at =210 nm (Separations), in sequence with an electrochemical detector (Interscience, Breda, The Netherlands) equipped with an analytical cell (Model 5010). All compounds leave the UV detector chemically intact, and so the electrochemically active components can be oxidized in the electrochemical cell. This type of electrochemical cell contains two separate analytical cells, which makes it possible to create a small window of applied potential. The detector 2 potential was set at 0.4 V, while the detector 1 potential was 0.3 V. This minimizes interfering peaks because only compounds with an oxidation potential from 0.3 to 0.4 V are recorded. Chromatographic separations were achieved using a Cp-Sper C8 column (250x4.6 mm) (Chrompack, Bergen op Zoom, The Netherlands). The mobile phase was a 0.01 M KH2PO4 buffer, pH=2.1, containing 11% acetonitrile and heptane sulphonic acid 0.4 g litre1.
In serum, all calibration graphs (containing six data points) were linear: for M3G the concentrations ranged from 25 to 580 ng ml1 (r=0.9992); for M6G from 5 to 100 ng ml1 (r=0.9982) and for morphine, from 5 to 90 ng ml1 (r=0.9963). On average, the quantitation limit was 5 ng ml1 for morphine and M6G and 25 ng ml1 for M3G. However, in individual samples the quality of the chromatogram was inspected and allowed for a lower threshold when peaks were clearly separated from baseline. In this concentration range, the intra-day precision was less than 10% for all compounds and the bias was about 5%.15 16 Standardized automated laboratory analysers measured serum concentrations of bilirubin and creatinine.
Morphine hydrochloride dose and M3G and M6G concentrations were converted to anhydrous morphine base equivalents using a molecular weight of 285 for morphine, 322 for morphine hydrochloride and 461 for the two glucuronide metabolites.
Modelling
Population parameter estimates were obtained using a non-linear mixed effects model. This model accounts for random between-subject parameter variability and residual variability (random effects) as well as between-subject parameter differences predicted by covariates (fixed effects). The population parameter variability in model parameters was modelled by an exponential variance model. The covariance between clearance, distribution volume and absorption half-life was incorporated into the model. A proportional term characterized the residual unknown variability for morphine. An additive and a proportional term characterized the residual unknown variability for M3G and M6G concentrations. The population mean parameters, between-subject variance and residual variances were estimated using NONMEM version V release 1.1.17 Estimation used the first-order conditional estimate method with the interaction option and ADVAN 6 with Tol=5. The convergence criterion was 3 significant digits. A Compaq Digital Fortran Version 6.6A compiler with Intel Celeron 333 MHz CPU (Intel, Santa Clara, CA, USA) under Microsoft Windows XP (Microsoft, Seattle, WA, USA) was used to compile NONMEM.
Differential equations were used to describe the pharmacokinetics of morphine and its metabolites.
CLT=CL2M3G+CL2M6G+CLEX
dCS/dt=(RATEINCSxCLT)/V
dM3G/dt=(CL2M3GxCSCLM3GxCM3G)/V3M
dM6G/dt=(CL2M6GxCSCLM6GxCM6G)/V6M
The model is shown in Figure 1. CLT is total morphine clearance, V is the volume of distribution for morphine, CS is morphine serum concentration, CL2M3G is formation clearance to M3G, CM3G is the serum M3G concentration, CL2M6G is formation clearance to M6G, CM6G is the serum M6G concentration, CLM3G is the elimination clearance of M3G, CLM6G is the elimination clearance of M6G, VM is the volume of distribution of glucuronide metabolites, CLEX is morphine clearance by other routes, and RATEIN is the morphine infusion rate.
|
The parameter values were standardized for a body weight of 70 kg using an allometric model:7 20
Pi=Pstdx(Wi/Wstd)PWR
where Pi is the parameter in the ith individual, Wi is the weight in the ith individual and Pstd is the parameter in an individual with a weight (Wstd) of 70 kg. The PWR exponent was 0.75 for clearance and 1 for distribution volumes.2023
Exponential functions were applied to describe age-related developmental changes in the formation of metabolites (CL2M3G, CL2M6G), clearance of metabolites (CLM3G, CLM6G) and morphine volume of distribution (Table 3B):
|
FCLMxG={1ßrfxEXP[PNA in daysxLn(2)/Trf]}
FV={1ßvolxEXP[PNA in daysxLn(2)/Tvol]}
where ßcl, ßrf and ßvol are parameters estimating the fraction below adult values of parameters predicted at birth; Tcl, Trf and Tvol describe the maturation half-lives of the age-related changes in the parameters. FCL2MxG, FCLMxG represent the formation and elimination clearances of either M3G or M6G and FV morphine volume as a fraction of standard 70 kg adult values, i.e. when AGE is sufficiently large that the exponential expression tends to zero.
The effect of altered renal function on CLM3G and CLM6G was modelled using an estimate of renal function in children older than 1 week. Renal function was standardized to a 40-yr-old adult male with a creatinine clearance of 6 litres h1 and a serum creatinine of 85.947 µmol litre1.24 This empirical model used age (PNA) as a covariate to predict creatinine production rate with scaling constant (Kage) for age:
FRF=85.947/creatininexEXP(KagexPNA/36540).
Serum bilirubin (µmol litre1) was used as a marker of hepatic function and its effect on CL2M3G and CL2M6G was modelled with an exponential function with a scaling constant (Kbili):
FBILI=EXP(bilirubinxKbili).
The clearance in a child with specific age, serum creatinine and bilirubin was then predicted by multiplying each of the covariate factors by the population parameter value for a standard 70 kg adult.
CL2M3G=CL2M3GstdxFCL2M3GxFBILI
CLM3G=CLM3GstdxFCLM3GxFRF.
The quality of fit of the pharmacokinetic model to the data was assessed by visual examination of plots of observed versus predicted concentrations. Models were nested and an improvement in the objective function was referred to the Chi-squared distribution to assess significance; e.g. an objective function change (OBJ) of 3.84 is significant at =0.05.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
|
|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The total body clearance (CLT) was 80% of that of adults by 6 months and 96% of that predicted in adults by 1 yr. Morphine HCl CLT and its rate of maturation fall between those described by McRorie and colleagues32 and those described by others,30 33 when their estimates are standardized to a 70-kg person with a power model (Table 3CC). Our estimates are for the anhydrous morphine base rather than sulphate or hydrochloride salts and were determined using a population-based analysis. Differences may also be related to the population studied and the nature of the illness within that population.5 McRorie and colleagues32 and Lynn and colleagues30 determined clearance by dividing infusion rate by steady-state concentration. Patients who did not achieve steady-state concentrations were excluded and it is unclear from their papers if the morphine salt used in the infusion and measured concentrations of morphine were corrected for molecular weight. We predict that morphine total clearance rises from 14.5 litres h1 per 70 kg at birth to 71 litres h1 per 70 kg in adults.
|
The volume of distribution increased exponentially with a maturation half-life of 26.3 days from 83 litres per 70 kg at birth to 136 (CV 117%) l/70 kg at 6 months. A literature review was unable to discern age related changes in volume of distribution.4 However, the methods used in the literature to determine volume of distribution vary greatly and it is difficult to compare estimates. Individual studies, such as that by Pokela and colleagues,36 report similar age-related changes to ours. The volume of distribution increased from 91 (SD 28) litres per 70 kg in neonates 14 days old, 126 (SD 56) litres per 70 kg at 860 days and 168 (SD 105) litres per 70 kg at 61180 days of age.
The metabolite volumes of distribution in neonates and children are unknown. Penson and colleagues18 report a volume of distribution for M3G (V3M) of 23.1 litres per 70 kg in adults. Adult estimates for the volume of distribution for M6G (V6M) are from 8.4 to 30 litres per 70 kg.19 3739 V6M is believed to be greater than V3M because of higher lipophilicity at physiological pH;40 consequently a V6M of 30 litres per 70 kg was empirically chosen. The goodness of fit was poorest for the prediction of serum metabolite concentration after the initial loading dose of morphine (Fig. 7) and may be attributable to fixing VM at a set value with no associated variability. The total elimination clearance of M3G (CLM3G) of 17.4 (CV 43%) litres h1 per 70 kg is greater than the renal M3G clearance described by Penson and colleagues37 [10.1 (SD 2.9) litres h1 70 kg] in adults but total urinary morphine and metabolite recovery was only 74.6% in that study. Penson and colleagues18 and Lotsch and colleagues39 report a CLM6G of 9.4 (SD 2.8) litres h1 per 70 kg and 9.24 (SD 1.68) litres h1 per 70 kg respectively, greater than our estimate of 5.8 (CV 73.8%) litres h1 per 70 kg in young children.
The morphine metabolites M3G and M6G are water-soluble compounds, enabling renal excretion. The time course of metabolite elimination clearance is similar to that of glomerular filtration rate (GFR), although clearance of morphine glucuronide metabolites is greater (Fig. 5). This may be attributable to renal tubular secretion35 41 42 and non-renal elimination.35 43 Changes in GFR are usually referenced to body surface area in children,25 a model that approximates the power model but uses 2/3 as the weight exponent. Attempts to use the Cockcroft and Gault models44 to predict creatinine production rate failed. An empirical formula based on age to predict creatinine production was used. Creatinine production increased with age (Kage 0.0141) as opposed to adults, in whom production decreases with age.44 The increase in children is assumed to be a consequence of increasing muscle bulk with age as opposed to the decrease in muscle bulk that occurs with age in adults. The maturation of GFR is commonly estimated by creatinine clearance. However, creatinine clearance (CrCl) may result in overestimation as GFR declines because of tubular secretion, changes in metabolic state altering creatinine production, and measurement errors at low concentrations significantly altering CrCl estimation. We demonstrated minimal effect attributable to altered renal function (based on creatinine production) because maturation of metabolite elimination clearance, which mirrored GFR maturation, was already accounted for.
Serum bilirubin was used as a marker of hepatic function. This is a very crude marker of hepatic function because serum concentrations are dependent on both formation and clearance of bilirubin. Bilirubin is metabolized in the liver by another glucuronosyltransferase, UGT1A1, and does not compete for the same metabolic pathway as morphine.1 Activity of this enzyme also increases immediately after birth, reaching adult values at 36 months.45 It was possible to relate bilirubin to metabolite formation. Formation clearance to M3G in a 1-yr-old child, for example, is reduced from 60 litres h1 per 70 kg when serum bilirubin is 5 µmol litre1 to 43 litres h1 per 70 kg when bilirubin is 180 µmol litre1.
Routes other than glucuronidation clear morphine in humans. Renal clearance of unmetabolized morphine may contribute up to 19% of CLT in infants younger than 3 months, 13% in older infants and 11% in adults.32 Sulphate metabolism for morphine and paracetamol is active in neonates and contributes approximately 6 litres h1 per 70 kg for paracetamol clearance in 1-yr-old children and adults.32 46 Faecal excretion and normorphine formation contribute minimally. We were unable to quantify elimination specifically by these other routes. Unaccounted for clearance of morphine contributed less than 5% in our analysis.
![]() |
Acknowledgements |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Pacifici GM, Sawe J, Kager L, Rane A. Morphine glucuronidation in human fetal and adult liver. Eur J Clin Pharmacol 1982; 22: 5538[ISI][Medline]
3 Pacifici GM, Franchi M, Giuliani L, Rane A. Development of the glucuronyltransferase and sulphotransferase towards 2-naphthol in human fetus. Dev Pharmacol Ther 1989; 14: 10814[ISI][Medline]
4 Kart T, Christrup LL, Rasmussen M. Recommended use of morphine in neonates, infants and children based on a literature review: Part 1Pharmacokinetics. Paediatr Anaesth 1997; 7: 511[ISI][Medline]
5 Lynn A, Nespeca MK, Bratton SL, Strauss SG, Shen DD. Clearance of morphine in postoperative infants during intravenous infusion: the influence of age and surgery. Anesth Analg 1998; 86: 95863[Abstract]
6 Faura CC, Collins SL, Moore RA, McQuay HJ. Systematic review of factors affecting the ratios of morphine and its major metabolites. Pain 1998; 74: 4353[CrossRef][ISI][Medline]
7 Holford NHG. A size standard for pharmacokinetics. Clin Pharmacokinet 1996; 30: 32932[ISI][Medline]
8 Anderson BJ, McKee AD, Holford NH. Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients. Clin Pharmacokinet 1997; 33: 31327[ISI][Medline]
9 Bouwmeester NJ, Anand KJ, van Dijk M, Hop WC, Boomsma F, Tibboel D. Hormonal and metabolic stress responses after major surgery in children aged 03 years: a double-blind, randomized trial comparing the effects of continuous versus intermittent morphine. Br J Anaesth 2001; 87: 3909
10 Bouwmeester NJ, van den Anker JN, Hop WC, Anand KJ, Tibboel D. Age- and therapy-related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants. Br J Anaesth 2003; 90: 64252
11 van Dijk M, de Boer JB, Koot HM, Tibboel D, Passchier J, Duivenvoorden HJ. The reliability and validity of the COMFORT scale as a postoperative pain instrument in 0- to 3-year-old infants. Pain 2000; 84: 36777[CrossRef][ISI][Medline]
12 van Dijk M, de Boer JB, Koot HM, et al. The association between physiological and behavioral pain measures in 0- to 3-year-old infants after major surgery. J Pain Symptom Manage 2001; 22: 6009[CrossRef][ISI][Medline]
13 van Dijk M, Peters JW, Bouwmeester NJ, Tibboel D. Are postoperative pain instruments useful for specific groups of vulnerable infants? Clin Perinatol 2002; 29: 46991, x[ISI][Medline]
14 van Dijk M, Koot HM, Saad HH, Tibboel D, Passchier J. Observational visual analog scale in pediatric pain assessment: useful tool or good riddance? Clin J Pain 2002; 18: 3106[CrossRef][ISI][Medline]
15 Kimenai PM. Clinical pharmacokinetics of nicomorphine. Metabolic conversion: an important aspect of drug action. Clinical Pharmacology. Nijmegen: Katholic University, 1996
16 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 Chromatogr 1991; 570: 30920[Medline]
17 Beal SL, Sheiner LB, Boeckmann A. Nonmem Users Guide. San Francisco: Division of Pharmacology, University of California, 1999
18 Penson RT, Joel SP, Clark S, Gloyne A, Slevin ML. Limited phase I study of morphine-3-glucuronide. J Pharm Sci 2001; 90: 18106[CrossRef][ISI][Medline]
19 Hanna MH, Peat SJ, Knibb AA, Fung C. Disposition of morphine-6-glucuronide and morphine in healthy volunteers. Br J Anaesth 1991; 66: 1037[Abstract]
20 Karalis V, Macheras P. Drug disposition viewed in terms of the fractal volume of distribution. Pharm Res 2002; 19: 696703[Medline]
21 Peters HP. Physiological correlates of size. In: Beck E, Birks HJB, Conner EF, eds. The Ecological Implications of Body Size. Cambridge: Cambridge University Press, 1983; 4853
22 West GB, Brown JH, Enquist BJ. A general model for the origin of allometric scaling laws in biology. Science 1997; 276: 1226
23 West GB, Brown JH, Enquist BJ. The fourth dimension of life: fractal geometry and allometric scaling of organisms. Science 1999; 284: 16779
24 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 3141[ISI][Medline]
25 Bergstein JM. Introduction to glomerular diseases. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. Philadelphia: W. B. Saunders, 2000; 15745
26 Anderson BJ, Meakin GH. Scaling for size: some implications for paediatric anaesthesia dosing. Paediatr Anaesth 2002; 12: 20519[CrossRef][ISI][Medline]
27 Chay PC, Duffy BJ, Walker JS. Pharmacokinetic-pharmacodynamic relationships of morphine in neonates. Clin Pharmacol Ther 1992; 51: 33442[ISI][Medline]
28 Hartley R, Green M, Quinn M, Levene MI. Pharmacokinetics of morphine infusion in premature neonates. Arch Dis Child 1993; 69: 558[Abstract]
29 Scott CS, Riggs KW, Ling EW, et al. Morphine pharmacokinetics and pain assessment in premature newborns. J Pediatr 1999; 135: 4239[ISI][Medline]
30 Lynn AM, Nespeca MK, Bratton SL, Shen DD. Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions. Pain 2000; 88: 8995[CrossRef][ISI][Medline]
31 Choonara IA, McKay P, Hain R, Rane A. Morphine metabolism in children. Br J Clin Pharmacol 1989; 28: 599604[ISI][Medline]
32 McRorie TI, Lynn AM, Nespeca MK, Opheim KE, Slattery JT. The maturation of morphine clearance and metabolism. Am J Dis Child 1992; 146: 9726[ISI][Medline]
33 Hunt A, Joel S, Dick G, Goldman A. Population pharmacokinetics of oral morphine and its glucuronides in children receiving morphine as immediate-release liquid or sustained-release tablets for cancer pain. J Pediatr 1999; 135: 4755[ISI][Medline]
34 Barrett DA, Barker DP, Rutter N, Pawula M, Shaw PN. Morphine, morphine-6-glucuronide and morphine-3-glucuronide pharmacokinetics in newborn infants receiving diamorphine infusions. Br J Clin Pharmacol 1996; 41: 5317[ISI][Medline]
35 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: 34454[ISI][Medline]
36 Pokela ML, Olkkola KT, Seppala T, Koivisto M. Age-related morphine kinetics in infants. Dev Pharmacol Ther 1993; 20: 2634[ISI][Medline]
37 Penson RT, Joel SP, Roberts M, Gloyne A, Beckwith S, Slevin ML. The bioavailability and pharmacokinetics of subcutaneous, nebulized and oral morphine-6-glucuronide. Br J Clin Pharmacol 2002; 53: 34754[CrossRef][ISI][Medline]
38 Osborne R, Thompson P, Joel S, Trew D, Patel N, Slevin M. The analgesic activity of morphine-6-glucuronide. Br J Clin Pharmacol 1992; 34: 1308[ISI][Medline]
39 Lotsch J, Weiss M, Kobal G, Geisslinger G. Pharmacokinetics of morphine-6-glucuronide and its formation from morphine after intravenous administration. Clin Pharmacol Ther 1998; 63: 62939[ISI][Medline]
40 Carrupt PA, Testa B, Bechalany A, el Tayar N, Descas P, Perrissoud D. Morphine 6-glucuronide and morphine 3-glucuronide as molecular chameleons with unexpected lipophilicity. J Med Chem 1991; 34: 12725[ISI][Medline]
41 Somogyi AA, Nation RL, Olweny C, et al. Plasma concentrations and renal clearance of morphine, morphine-3-glucuronide and morphine-6-glucuronide in cancer patients receiving morphine. Clin Pharmacokinet 1993; 24: 41320[ISI][Medline]
42 Van Crugten JT, Sallustio BC, Nation RL, Somogyi AA. Renal tubular transport of morphine, morphine-6-glucuronide, and morphine-3-glucuronide in the isolated perfused rat kidney. Drug Metab Dispos 1991; 19: 108792[Abstract]
43 Milne RW, McLean CF, Mather LE, et al. Influence of renal failure on the disposition of morphine, morphine-3-glucuronide and morphine-6-glucuronide in sheep during intravenous infusion with morphine. J Pharmacol Exp Ther 1997; 282: 77986
44 Bjornsson TD. Use of serum creatinine concentrations to determine renal function. Clin Pharmacokinet 1979; 4: 20022[ISI][Medline]
45 Onishi S, Kawade N, Itoh S, Isobe K, Sugiyama S. Postnatal development of uridine diphosphate glucuronyltransferase activity towards bilirubin and 2-aminophenol in human liver. Biochem J 1979; 184: 7057[ISI][Medline]
46 van der Marel CD, Anderson BJ, van Lingen RA, et al. Paracetamol and metabolite pharmacokinetics in infants. Eur J Clin Pharmacol 2003: 59: 24351
47 van Lingen RA, Simons SH, Anderson BJ, Tibboel D. The effects of analgesia in the vulnerable infant during the perinatal period. Clin Perinatol 2002; 29: 51134[ISI][Medline]