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Urinary propofol metabolites in early life after single intravenous bolus
British Journal of Anaesthesia 101 (6): 827–31 (2008)
doi:10.1093/bja/aen276
Advance Access publication October 3, 2008
PAEDIATRICS Urinary propofol metabolites in early life after single intravenous bolus K. Allegaert1*, J. Vancraeynest2, M. Rayyan1, J. de Hoon2, V. Cossey1, G. Naulaers1 and R. Verbesselt2 1
Neonatal Intensive Care Unit and 2Center for Clinical Pharmacology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium *Corresponding author. E-mail: [email protected]
Methods. Twenty-four hours urine collections were sampled after a single i.v. bolus of propofol (3 mg kg21) in neonates undergoing procedural sedation. Clinical characteristics (PMA, PNA, weight, and cardiopathy) were recorded. Urine metabolites [propofol glucuronide (PG), 1- and 4-quinol glucuronide (QG)] were quantified using high-pressure liquid chromatography. Urine recovery (% administered dose) and the contribution of PG and QG to urinary elimination were calculated. Data were reported by median and range, analysed by Mann–Whitney U or Spearman’s rank. Results. Eleven neonates (median PNA 11 days, PMA 38 weeks) were included. Median propofol metabolite recovery was 64% (range 34–98%). PG contributed 34% (range 8–67%) and QG 65% (range 33–92%). There was no significant correlation between either PMA, PNA, or cardiopathy and propofol metabolites. Compared with adults, the contribution of PG (34% vs 77%) was lower and the contribution of QG (65% vs 22%) was higher in neonates. Conclusions. Propofol metabolism in neonates differs from adults, reflecting the agedependent limited glucuronidation capacity. Hydroxylation to quinol metabolites already contributes to propofol metabolism. These differences likely explain the PMA- and PNA-dependent reduced propofol clearance in neonates. Br J Anaesth 2008; 101: 827–31 Keywords: age factors; liver, metabolism; metabolism, urinary conjugates; pharmacokinetics, propofol; potency, anaesthetic, age factors Accepted for publication: August 19, 2008
Disposition of propofol has been extensively studied in different populations of adult and paediatric age, but observations in neonates are still limited. Propofol clearance in neonates is significantly lower compared with children and displays extensive interindividual variability.1 – 7 Covariates of the interindividual variability of propofol clearance in neonates are postnatal age (PNA) and postmenstrual age (PMA).7 Since propofol clearance almost exclusively depends on biotransformation, it is anticipated that agedependent differences in propofol clearance reflect quantitative or qualitative differences in propofol metabolism. In adults, propofol undergoes either glucuronidation [mainly through UDP-glucuronosyltransferase 1A9,
resulting in propofol glucuronide, PG] or hydroxylation [mainly through cytochrome P450 (CYP) 2B6, resulting in 1- or 4-quinol, 1-Q and 4-Q] with subsequent glucuronidation [(1-quinol glucuronide (1-QG), 4-quinol glucuronide (4-QG)] or sulphation [4-quinol sulphate (4-QS)], respectively. After i.v. bolus administration (3 mg kg21) in adults, PG is the major metabolite while urinary excretion of unchanged propofol contributes only marginally (,1%) to propofol clearance.5 6 The contribution of hydroxylation is higher during continuous i.v. administration of propofol in adults.5 6 During paediatric life, hepatic drug metabolism displays isoenzyme-dependent ontogeny which is most prominent
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Background. Propofol clearance is lower in neonates than in adults and displays extensive interindividual variability, in part explained by postmenstrual age (PMA) and postnatal age (PNA). Since propofol is almost exclusively cleared metabolically, urinary propofol metabolites were determined in early life and compared with similar observations reported in adults.
Allegaert et al.
in early life.8 We are unaware of any in vivo observations on CYP2B6 activity in neonates while—based on observations on acetaminophen, tramadol, and morphine disposition in neonates—glucuronidation activity has previously been shown to depend on PNA and PMA.9 – 11 We therefore sampled 24 h urine collections in neonates and young infants after i.v. bolus administration of propofol to document covariates of propofol metabolism. Although differenced analytical techniques were used, at least the clinical model (24 h urine collections after single i.v. bolus administration, 3 mg kg21) enabled us to compare observations in neonates with reported observations of Sneyd and colleagues6 in adults (n¼6).
Methods
Neonates were included after approval of the study by the ethical board of the University Hospitals Leuven, Belgium, and after informed written consent of the parents. Neonates in whom propofol was prescribed to facilitate elective chest tube removal were considered for inclusion in this study on the condition that a urinary bladder catheter was in place.3 7 After i.v. bolus administration of propofol, urine was collected for 24 h after i.v. bolus administration in four consecutive 6 h aliquots. For every collection period, the urine volume was registered and a 5 ml urine sample was stored at 2208C until analysis. Just before the chest tube removal, propofol (3 mg kg21 i.v. bolus, Diprivanw, Braun, Diegem, Belgium) was administered in addition to the analgesics already administered by continuous (fentanyl or tramadol) or intermittent (acetaminophen) infusion.12 Clinical characteristics recorded at inclusion were: PMA (weeks), gestational age (weeks), PNA (days), weight, creatinaemia, indication for the chest tube placement, and presence of a congenital cardiopathy.
Drug assay PG, 1-QG, and 4-QG were quantified in urine by high performance liquid chromatography after a one-fifth dilution in the mobile phase, adding thymol as an internal standard and direct injection onto the analytical column (2504.6 mm ID) filled with Spherisorb ODS 5 mm. A gradient elution was applied starting at 10/90 (v/v), acetonitrile/0.1% trifluoroacetic acid, increasing to 85/15 over 35 min, maintaining for 5 min at this composition and returning over 10 min to the initial condition 10/90 and equilibrating for a further 10 min before next injection (metabolites provided by J. Guitton, Lyon, France). A good separation was obtained between the PG, 1-QG, 4-QG, and thymol, using UV detection at 265 nm. Quantification was performed by single-point calibration, because of the limited amount available of the
Data reporting and statistics Urine metabolites (mg litre21) were converted to molar concentrations (mmol litre21) (molecular weights: P¼178.27, PG¼354.39, and 1-QG or 4-QG¼370.38) to calculate total propofol equivalent urine elimination and the proportional contribution of each of the metabolites to overall renal elimination of propofol equivalent over the 24 h period. Statistical analysis was performed by MedCalcw software (Mariakerke, Belgium). Urine metabolite observations and clinical characteristics are reported by median and range when non-normal distribution (Kolmogorov – Smirnov test) was documented. Spearman’s rank correlation was used to explore the impact of PNA and PMA on the contribution of the various metabolites retrieved in the 24 h urine collections. Mann – Whitney U-test was used to assess the impact of PNA (dichotomous, early, or late neonatal life, i.e. younger or older than 10 days PNA) or associated cardiopathy (yes/no) on the propofol metabolite excretion profile. Finally, observations in neonates were compared with earlier reported observations in six adults (Mann – Whitney U-test).6 A P-value of ,0.05 was considered significant.
Results Eleven neonates and young infants were included. Clinical characteristics and the indication for initial chest tube placement are provided in Table 1. Median urine recovery of propofol equivalents after single i.v. bolus administration in the 24 h urine collection was 64% (34 – 98%). PG contributed 34% (8 – 67%) whereas QG (sum of 1-QG and 4-QG) contributed 65% (33 – 92%) to overall propofol metabolite elimination, resulting in a PG/QG ratio of Table 1 Clinical characteristics of included neonates, reported by median and range or number of cases Postnatal age Postmenstrual age Weight at inclusion Creatinaemia Urine output, 6 h aliquot Propofol dose Medical condition for initial chest tube placement Non-cardiac Pneumothorax Congenital diaphragmatic hernia Cardiac Coarctectomy Banding arteria pulmonalis Clipping patent ductus arteriosus
828
11 (4 –60) days 38 (27 –46) weeks 3.240 (0.915 – 4.0) kg 0.53 (0.37 –1.02) mg dl21 75 (21 –196) ml 9 (3 –11) mg 5 1 4 6 3 2 1
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Clinical characteristics, ethics, procedural sedation, and sampling
glucuronides, using peak height ratios of the different compounds over thymol as the internal standard. Injection linearity was found in the range of 0.1–100 mg ml21 and lower limit of quantification was 0.1 mg ml21. Coefficients of variation of intra- and interday precision and accuracy were below 15%.13 14 In the absence of available 4-QS for standardization, we were unable to quantify this metabolite.
Propofol metabolism in early life
Table 2 Fraction (%) of the dose retrieved in urine in terms of the total metabolites of propofol eliminated during each 6 h collection interval for all individual observations with median values
14 Observation collected in an adult Observation collected in a neonate
12 Case
0 –6 h
6– 12 h
12– 18 h
18– 24 h
a b c d e f g h i j k Median (%)
20 3 21 4 36 47 3 64 25 47 24 27
3 8 2 42 19 13 14 31 8 20 6 15
16 14 13 28 14 4 15 1 2 13 11 12
46 17 29 17 9 3 20 2 0 6 13 15
PG/QG
10 8 6 4 2 0 Adult
Recovery 24 h urine (%) PG/propofol total (%) QG/propofol total (%) 1-QG/propofol total (%) 4-QG/propofol total (%) Ratio PG/QG
Adults6
Neonates
P-value
53 (34 –58) 77 (72 –93) 22 (7 –28) 13 (7 –15) 10 (0 –13) 3.46 (2.57 –13.3)
64 (34 –98) 34 (8 –67) 65 (33 –92) 24 (5 –60) 33 (16 –67) 0.34 (0.09 –2.4)
0.15 ,0.001 ,0.0001 0.18 ,0.0001 ,0.001
0.37 (0.09– 2.0). Percentages (eliminated/total dose administered) of the dose retrieved in the urine in terms of the total metabolites of propofol eliminated during a given 6 h collection interval are provided for all individual observations and median values in Table 2. The interindividual variability in propofol metabolism, reflected in the contribution of PG and QG to overall urinary elimination and in the PG/QG ratio, in neonates could not be explained by either PMA or PNA (Spearman’s rank, both P-values .0.05). There were no differences in urine propofol metabolite profiles between collections in early vs late neonatal life, nor in neonates with or without cardiopathy (both P-values .0.05). Compared with observations on urine propofol metabolite profile in adults, the contribution of PG was significantly lower (34% in neonates, 77% in adults, P,0.001) and the contribution of QG was significantly higher (65% vs 22%, P,0.0001), resulting in a significantly lower PG/QG ratio in neonates (Table 3 and Fig. 1).
Discussion On the basis of observations collected in early life, it was documented that propofol mainly undergoes hydroxylation with only limited PG production resulting in a median
Fig 1 Individual 24 h urine PG/QG ratios and the median values (bars) after i.v. bolus administration of 3 mg kg21 propofol as documented in six adults by Sneyd and colleagues6 and 11 neonates described in this study are both presented. PG, propofol glucuronide; QG, sum of 1- and 4-quinol glucuronide.
propofol metabolite recovery of 64% in the first 24 h urine collection i.v. bolus administration. These observations in neonates differ significantly from those reported previously for six adults (Table 2).6 The propofol metabolic profile in adults in part depends on the dose administered and on whether an i.v. bolus or a continuous i.v. administration approach was used. Compared with Sneyd and colleagues (3 mg kg21 bolus), a subanaesthetic dose (0.47 mg kg21 bolus) resulted in a higher dose cleared by hydroxylation whereas Favetta and colleagues5 documented that the contribution of hydroxylation to overall propofol elimination was higher during continuous administration.15 The differences in propofol metabolism depending on doses and dosing regimes suggest that glucuronidation acts as a high capacity metabolic pathway with limited specificity once glucuronidation activity is mature whereas hydroxylation (CYP2B6) is more substrate-specific, but has a more limited capacity. To make the observations comparable with available data in adults, we used a clinical approach very similar (i.v. bolus administration of propofol, 3 mg kg21, followed by 24 h urine collections) to that used by Sneyd and colleagues.6 Using this approach, it was documented that the metabolic profile in neonates is very different from adults. The reduced contribution of PG to overall propofol urinary elimination in neonates likely reflects the limited glucuronidation capacity in early life, which was also observed for acetaminophen, tramadol, and morphine glucuronidation.9 – 11 However, in contrast to these water-soluble compounds, propofol cannot be eliminated by the renal route before biotransformation, resulting in delayed clearance through hydroxylation with subsequent conjugation (either glucuronidation or sulphation). In the absence of metabolic clearance because of the age-dependent limited
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Table 3 Propofol metabolite retrieval in 24 h urine collections in neonates compared with adults after single i.v. bolus administration. Observations for adults as reported by Sneyd and colleagues6 have been recalculated after exclusion of the 4-QS contribution. Observations reported by median and range. P, propofol; PG, propofol glucuronide; 1- or 4-QG, 1- or 4-quinol glucuronide; QG, sum of 1- and 4-quinol glucuronide
Neonate
Allegaert et al.
Funding The clinical research of K.A. is supported by a Fundamental Clinical Investigatorship (1800209 N) from the Fund for Scientific Research, Flanders (Belgium) (F.W.O. Vlaanderen).
Acknowledgement We thank J. Guitton (Lyon, France) for kindly providing the propofol metabolites.
References 1 Rigby-Jones AE, Nolan JA, Priston MJ, Wright PM, Sneyd JR, Wolf AR. Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit. Anesthesiology 2002; 97: 1393 – 400 2 Shangguan WN, Lian Q, Aarons L, et al. Pharmacokinetics of single bolus of propofol in Chinese children of different ages. Anesthesiology 2006; 104: 27 – 32 3 Allegaert K, de Hoon J, Verbesselt R, Naulaers G, Murat I. Maturational pharmacokinetics of single intravenous bolus of propofol. Paediatr Anaesth 2007; 17: 1028 –34 4 Raoof AA, van Obbergh LJ, Verbeeck RK. Propofol pharmacokinetics in children with biliary atresia. Br J Anaesth 1995; 74: 46–9 5 Favetta P, Degoute CS, Perdrix JP, Dufresne C, Boulieu R, Guitton J. Propofol metabolites in man following propofol induction and maintenance. Br J Anaesth 2002; 88: 653– 8 6 Sneyd JR, Simons PJ, Wright B. Use of proton NMR spectroscopy to measure propofol metabolites in the urine of the female Caucasian patient. Xenobiotica 1994; 24: 1021 – 8 7 Allegaert K, Peeters MY, Verbesselt R, et al. Interindividual variability in propofol pharmacokinetics in preterm and term neonates. Br J Anaesth 2007; 99: 864 – 70 8 Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology— drug disposition, action, and therapy in infants and children. N Engl J Med 2003; 349: 1157– 67 9 Allegaert K, de Hoon J, Verbesselt R, et al. Intra- and interindividual variability of glucuronidation of paracetamol during repeated administration of propacetamol in neonates. Acta Paediatr 2005; 94: 1273 – 9 10 Allegaert K, Vanhole C, Vermeersch S, Rayyan M, Verbesselt R, de Hoon J. Both postnatal and postmenstrual age contribute to the interindividual variability in tramadol glucuronidation in neonates. Early Hum Dev 2008; 84: 325 – 30 11 Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH. Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. Br J Anaesth 2004; 92: 208 – 17 12 Allegaert K, Tibboel D, Naulaers G, et al. Systematic evaluation of pain in neonates: effect on the number of intravenous analgesics prescribed. Eur J Clin Pharmacol 2003; 59: 87 –90 13 Favetta P, Guitton J, Degoute CS, Van Daele L, Boulieu R. High-performance liquid chromatographic assay to detect hydroxylate and conjugate metabolites of propofol in human urine. J Chromatogr B Biomed Sci Appl 2000; 742: 25 – 35 14 Vree TB, Lagerwerf AJ, Bleeker CP, de Grood PM. Direct highperformance liquid chromatography determination of propofol and its metabolite quinol with their glucuronide conjugates and preliminary pharmacokinetics in plasma and urine of man. J Chromatogr Biomed Sci Appl 1999; 721: 217 – 28
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glucuronidation capacity, propofol undergoes hydroxylation to 1- and 4-quinol metabolites. On the basis of the current observations on in vivo urinary propofol metabolism, that hydroxylation (likely CYP2B6 dependent) is already present in neonates, which confirms a recent in vitro study on CYP2B6 activity in hepatic and renal microsomal fractions in neonates.16 17 The current data hereby support a cautious use of propofol in neonates since the previously described overall reduced propofol elimination clearance in neonates has been explained by maturational differences in metabolic capacity and by extensive interindividual variability in propofol metabolism in neonates.7 The extensive interindividual variability in propofol biotransformation in neonates could not be explained by the covariates (PMA, PNA, and cardiopathy) evaluated in this study. Phenotypic variation in drug metabolism depends on constitutional, genetic, and environmental factors, but in early life, mainly reflects isoenzyme-specific ontogeny.8 Besides age, covariates such as genetic polymorphisms or disease characteristics may be involved in propofol metabolism. Propofol hydroxylation is mainly mediated by CYP2B6. This isoenzyme displays genetic polymorphisms and can contribute to interindividual variability of drug metabolism in neonates.17 Liver blood flow is another significant covariate of propofol clearance during continuous administration in critically ill adults,5 but data on the agedependent hepatic blood flow in neonates are limited.18 19 The impact of various covariates (age, disease characteristics, and polymorphisms) on interindividual variability in propofol metabolism in neonates remains to be established. Finally, it was recently documented that tubular reabsorption of propofol and its metabolites by the kidney is a major contributor to elimination during continuous administration of propofol in adults that results in propofol metabolites in urine up to 60 h after administration.20 It is therefore striking that in the i.v. bolus model evaluated, the median recovery of propofol metabolites in the first 24 h urine collection is similar in neonates and adults. This might be explained by the limited renal tubular reabsorption in early life compared with adulthood, resulting in renal elimination after glomerular filtration instead of tubular reabsorption, compensating for the limited metabolic capacity in early life.8 20 In conclusion, propofol metabolism in neonates differs profoundly from adults. The current observations are in line with the extensive interindividual variability in propofol metabolic clearance described in early life. On the basis of the extensive variability in early life, this drug should be used cautiously in neonates since accumulation is more likely to occur. The present findings reflect the age-dependent limited glucuronidation capacity while CYP2B6-mediated propofol hydroxylation already contributes to propofol metabolism in neonates. Covariates of the extensive interindividual variability in propofol metabolites in early life were not evident.
Propofol metabolism in early life
15 Simons PJ, Cockshott ID, Douglas EJ, Gordon EA, Hopkins KJ, Rowland M. Disposition in male volunteers of a subanaesthetic intravenous dose of an oil in water emulsion of 14C-propofol. Xenobiotica 1988; 18: 429 – 40 16 Oda Y, Hamaoka N, Hiroi T, et al. Involvement of human liver cytochrome P4502B6 in the metabolism of propofol. Br J Clin Pharmacol 2001; 51: 281 – 5 17 Aleksa K, Matsell D, Krausz K, Gelboin H, Ito S, Koren G. Cytochrome P450 3A and 2B6 in the developing kidney: implications for ifosfamide nephrotoxicity. Pediatr Nephrol 2005; 20: 872–85
18 Allegaert K, Van den Anker JN, de Hoon JN, et al. Covariates of tramadol disposition in the first months of life. Br J Anaesth 2008; 100: 525 – 32 19 Peeters MY, Aarts LP, Boom FA, et al. Pilot study on the influence of liver blood flow and cardiac output on the clearance of propofol in critically ill patients. Eur J Clin Pharmacol 2008; 64: 329 – 34 20 Bleeker C, Vree T, Lagerwerf A, Willems-van Bree E. Recovery and long-term renal excretion of propofol, its glucuronide, and two di-isopropylquinol glucuronides after propofol infusion during surgery. Br J Anaesth 2008; 101: 207 – 12
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831
doi:10.1093/bja/aen276
Advance Access publication October 3, 2008
PAEDIATRICS Urinary propofol metabolites in early life after single intravenous bolus K. Allegaert1*, J. Vancraeynest2, M. Rayyan1, J. de Hoon2, V. Cossey1, G. Naulaers1 and R. Verbesselt2 1
Neonatal Intensive Care Unit and 2Center for Clinical Pharmacology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium *Corresponding author. E-mail: [email protected]
Methods. Twenty-four hours urine collections were sampled after a single i.v. bolus of propofol (3 mg kg21) in neonates undergoing procedural sedation. Clinical characteristics (PMA, PNA, weight, and cardiopathy) were recorded. Urine metabolites [propofol glucuronide (PG), 1- and 4-quinol glucuronide (QG)] were quantified using high-pressure liquid chromatography. Urine recovery (% administered dose) and the contribution of PG and QG to urinary elimination were calculated. Data were reported by median and range, analysed by Mann–Whitney U or Spearman’s rank. Results. Eleven neonates (median PNA 11 days, PMA 38 weeks) were included. Median propofol metabolite recovery was 64% (range 34–98%). PG contributed 34% (range 8–67%) and QG 65% (range 33–92%). There was no significant correlation between either PMA, PNA, or cardiopathy and propofol metabolites. Compared with adults, the contribution of PG (34% vs 77%) was lower and the contribution of QG (65% vs 22%) was higher in neonates. Conclusions. Propofol metabolism in neonates differs from adults, reflecting the agedependent limited glucuronidation capacity. Hydroxylation to quinol metabolites already contributes to propofol metabolism. These differences likely explain the PMA- and PNA-dependent reduced propofol clearance in neonates. Br J Anaesth 2008; 101: 827–31 Keywords: age factors; liver, metabolism; metabolism, urinary conjugates; pharmacokinetics, propofol; potency, anaesthetic, age factors Accepted for publication: August 19, 2008
Disposition of propofol has been extensively studied in different populations of adult and paediatric age, but observations in neonates are still limited. Propofol clearance in neonates is significantly lower compared with children and displays extensive interindividual variability.1 – 7 Covariates of the interindividual variability of propofol clearance in neonates are postnatal age (PNA) and postmenstrual age (PMA).7 Since propofol clearance almost exclusively depends on biotransformation, it is anticipated that agedependent differences in propofol clearance reflect quantitative or qualitative differences in propofol metabolism. In adults, propofol undergoes either glucuronidation [mainly through UDP-glucuronosyltransferase 1A9,
resulting in propofol glucuronide, PG] or hydroxylation [mainly through cytochrome P450 (CYP) 2B6, resulting in 1- or 4-quinol, 1-Q and 4-Q] with subsequent glucuronidation [(1-quinol glucuronide (1-QG), 4-quinol glucuronide (4-QG)] or sulphation [4-quinol sulphate (4-QS)], respectively. After i.v. bolus administration (3 mg kg21) in adults, PG is the major metabolite while urinary excretion of unchanged propofol contributes only marginally (,1%) to propofol clearance.5 6 The contribution of hydroxylation is higher during continuous i.v. administration of propofol in adults.5 6 During paediatric life, hepatic drug metabolism displays isoenzyme-dependent ontogeny which is most prominent
# The Board of Management and Trustees of the British Journal of Anaesthesia 2008. All rights reserved. For Permissions, please e-mail: [email protected]
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Background. Propofol clearance is lower in neonates than in adults and displays extensive interindividual variability, in part explained by postmenstrual age (PMA) and postnatal age (PNA). Since propofol is almost exclusively cleared metabolically, urinary propofol metabolites were determined in early life and compared with similar observations reported in adults.
Allegaert et al.
in early life.8 We are unaware of any in vivo observations on CYP2B6 activity in neonates while—based on observations on acetaminophen, tramadol, and morphine disposition in neonates—glucuronidation activity has previously been shown to depend on PNA and PMA.9 – 11 We therefore sampled 24 h urine collections in neonates and young infants after i.v. bolus administration of propofol to document covariates of propofol metabolism. Although differenced analytical techniques were used, at least the clinical model (24 h urine collections after single i.v. bolus administration, 3 mg kg21) enabled us to compare observations in neonates with reported observations of Sneyd and colleagues6 in adults (n¼6).
Methods
Neonates were included after approval of the study by the ethical board of the University Hospitals Leuven, Belgium, and after informed written consent of the parents. Neonates in whom propofol was prescribed to facilitate elective chest tube removal were considered for inclusion in this study on the condition that a urinary bladder catheter was in place.3 7 After i.v. bolus administration of propofol, urine was collected for 24 h after i.v. bolus administration in four consecutive 6 h aliquots. For every collection period, the urine volume was registered and a 5 ml urine sample was stored at 2208C until analysis. Just before the chest tube removal, propofol (3 mg kg21 i.v. bolus, Diprivanw, Braun, Diegem, Belgium) was administered in addition to the analgesics already administered by continuous (fentanyl or tramadol) or intermittent (acetaminophen) infusion.12 Clinical characteristics recorded at inclusion were: PMA (weeks), gestational age (weeks), PNA (days), weight, creatinaemia, indication for the chest tube placement, and presence of a congenital cardiopathy.
Drug assay PG, 1-QG, and 4-QG were quantified in urine by high performance liquid chromatography after a one-fifth dilution in the mobile phase, adding thymol as an internal standard and direct injection onto the analytical column (2504.6 mm ID) filled with Spherisorb ODS 5 mm. A gradient elution was applied starting at 10/90 (v/v), acetonitrile/0.1% trifluoroacetic acid, increasing to 85/15 over 35 min, maintaining for 5 min at this composition and returning over 10 min to the initial condition 10/90 and equilibrating for a further 10 min before next injection (metabolites provided by J. Guitton, Lyon, France). A good separation was obtained between the PG, 1-QG, 4-QG, and thymol, using UV detection at 265 nm. Quantification was performed by single-point calibration, because of the limited amount available of the
Data reporting and statistics Urine metabolites (mg litre21) were converted to molar concentrations (mmol litre21) (molecular weights: P¼178.27, PG¼354.39, and 1-QG or 4-QG¼370.38) to calculate total propofol equivalent urine elimination and the proportional contribution of each of the metabolites to overall renal elimination of propofol equivalent over the 24 h period. Statistical analysis was performed by MedCalcw software (Mariakerke, Belgium). Urine metabolite observations and clinical characteristics are reported by median and range when non-normal distribution (Kolmogorov – Smirnov test) was documented. Spearman’s rank correlation was used to explore the impact of PNA and PMA on the contribution of the various metabolites retrieved in the 24 h urine collections. Mann – Whitney U-test was used to assess the impact of PNA (dichotomous, early, or late neonatal life, i.e. younger or older than 10 days PNA) or associated cardiopathy (yes/no) on the propofol metabolite excretion profile. Finally, observations in neonates were compared with earlier reported observations in six adults (Mann – Whitney U-test).6 A P-value of ,0.05 was considered significant.
Results Eleven neonates and young infants were included. Clinical characteristics and the indication for initial chest tube placement are provided in Table 1. Median urine recovery of propofol equivalents after single i.v. bolus administration in the 24 h urine collection was 64% (34 – 98%). PG contributed 34% (8 – 67%) whereas QG (sum of 1-QG and 4-QG) contributed 65% (33 – 92%) to overall propofol metabolite elimination, resulting in a PG/QG ratio of Table 1 Clinical characteristics of included neonates, reported by median and range or number of cases Postnatal age Postmenstrual age Weight at inclusion Creatinaemia Urine output, 6 h aliquot Propofol dose Medical condition for initial chest tube placement Non-cardiac Pneumothorax Congenital diaphragmatic hernia Cardiac Coarctectomy Banding arteria pulmonalis Clipping patent ductus arteriosus
828
11 (4 –60) days 38 (27 –46) weeks 3.240 (0.915 – 4.0) kg 0.53 (0.37 –1.02) mg dl21 75 (21 –196) ml 9 (3 –11) mg 5 1 4 6 3 2 1
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Clinical characteristics, ethics, procedural sedation, and sampling
glucuronides, using peak height ratios of the different compounds over thymol as the internal standard. Injection linearity was found in the range of 0.1–100 mg ml21 and lower limit of quantification was 0.1 mg ml21. Coefficients of variation of intra- and interday precision and accuracy were below 15%.13 14 In the absence of available 4-QS for standardization, we were unable to quantify this metabolite.
Propofol metabolism in early life
Table 2 Fraction (%) of the dose retrieved in urine in terms of the total metabolites of propofol eliminated during each 6 h collection interval for all individual observations with median values
14 Observation collected in an adult Observation collected in a neonate
12 Case
0 –6 h
6– 12 h
12– 18 h
18– 24 h
a b c d e f g h i j k Median (%)
20 3 21 4 36 47 3 64 25 47 24 27
3 8 2 42 19 13 14 31 8 20 6 15
16 14 13 28 14 4 15 1 2 13 11 12
46 17 29 17 9 3 20 2 0 6 13 15
PG/QG
10 8 6 4 2 0 Adult
Recovery 24 h urine (%) PG/propofol total (%) QG/propofol total (%) 1-QG/propofol total (%) 4-QG/propofol total (%) Ratio PG/QG
Adults6
Neonates
P-value
53 (34 –58) 77 (72 –93) 22 (7 –28) 13 (7 –15) 10 (0 –13) 3.46 (2.57 –13.3)
64 (34 –98) 34 (8 –67) 65 (33 –92) 24 (5 –60) 33 (16 –67) 0.34 (0.09 –2.4)
0.15 ,0.001 ,0.0001 0.18 ,0.0001 ,0.001
0.37 (0.09– 2.0). Percentages (eliminated/total dose administered) of the dose retrieved in the urine in terms of the total metabolites of propofol eliminated during a given 6 h collection interval are provided for all individual observations and median values in Table 2. The interindividual variability in propofol metabolism, reflected in the contribution of PG and QG to overall urinary elimination and in the PG/QG ratio, in neonates could not be explained by either PMA or PNA (Spearman’s rank, both P-values .0.05). There were no differences in urine propofol metabolite profiles between collections in early vs late neonatal life, nor in neonates with or without cardiopathy (both P-values .0.05). Compared with observations on urine propofol metabolite profile in adults, the contribution of PG was significantly lower (34% in neonates, 77% in adults, P,0.001) and the contribution of QG was significantly higher (65% vs 22%, P,0.0001), resulting in a significantly lower PG/QG ratio in neonates (Table 3 and Fig. 1).
Discussion On the basis of observations collected in early life, it was documented that propofol mainly undergoes hydroxylation with only limited PG production resulting in a median
Fig 1 Individual 24 h urine PG/QG ratios and the median values (bars) after i.v. bolus administration of 3 mg kg21 propofol as documented in six adults by Sneyd and colleagues6 and 11 neonates described in this study are both presented. PG, propofol glucuronide; QG, sum of 1- and 4-quinol glucuronide.
propofol metabolite recovery of 64% in the first 24 h urine collection i.v. bolus administration. These observations in neonates differ significantly from those reported previously for six adults (Table 2).6 The propofol metabolic profile in adults in part depends on the dose administered and on whether an i.v. bolus or a continuous i.v. administration approach was used. Compared with Sneyd and colleagues (3 mg kg21 bolus), a subanaesthetic dose (0.47 mg kg21 bolus) resulted in a higher dose cleared by hydroxylation whereas Favetta and colleagues5 documented that the contribution of hydroxylation to overall propofol elimination was higher during continuous administration.15 The differences in propofol metabolism depending on doses and dosing regimes suggest that glucuronidation acts as a high capacity metabolic pathway with limited specificity once glucuronidation activity is mature whereas hydroxylation (CYP2B6) is more substrate-specific, but has a more limited capacity. To make the observations comparable with available data in adults, we used a clinical approach very similar (i.v. bolus administration of propofol, 3 mg kg21, followed by 24 h urine collections) to that used by Sneyd and colleagues.6 Using this approach, it was documented that the metabolic profile in neonates is very different from adults. The reduced contribution of PG to overall propofol urinary elimination in neonates likely reflects the limited glucuronidation capacity in early life, which was also observed for acetaminophen, tramadol, and morphine glucuronidation.9 – 11 However, in contrast to these water-soluble compounds, propofol cannot be eliminated by the renal route before biotransformation, resulting in delayed clearance through hydroxylation with subsequent conjugation (either glucuronidation or sulphation). In the absence of metabolic clearance because of the age-dependent limited
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Table 3 Propofol metabolite retrieval in 24 h urine collections in neonates compared with adults after single i.v. bolus administration. Observations for adults as reported by Sneyd and colleagues6 have been recalculated after exclusion of the 4-QS contribution. Observations reported by median and range. P, propofol; PG, propofol glucuronide; 1- or 4-QG, 1- or 4-quinol glucuronide; QG, sum of 1- and 4-quinol glucuronide
Neonate
Allegaert et al.
Funding The clinical research of K.A. is supported by a Fundamental Clinical Investigatorship (1800209 N) from the Fund for Scientific Research, Flanders (Belgium) (F.W.O. Vlaanderen).
Acknowledgement We thank J. Guitton (Lyon, France) for kindly providing the propofol metabolites.
References 1 Rigby-Jones AE, Nolan JA, Priston MJ, Wright PM, Sneyd JR, Wolf AR. Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit. Anesthesiology 2002; 97: 1393 – 400 2 Shangguan WN, Lian Q, Aarons L, et al. Pharmacokinetics of single bolus of propofol in Chinese children of different ages. Anesthesiology 2006; 104: 27 – 32 3 Allegaert K, de Hoon J, Verbesselt R, Naulaers G, Murat I. Maturational pharmacokinetics of single intravenous bolus of propofol. Paediatr Anaesth 2007; 17: 1028 –34 4 Raoof AA, van Obbergh LJ, Verbeeck RK. Propofol pharmacokinetics in children with biliary atresia. Br J Anaesth 1995; 74: 46–9 5 Favetta P, Degoute CS, Perdrix JP, Dufresne C, Boulieu R, Guitton J. Propofol metabolites in man following propofol induction and maintenance. Br J Anaesth 2002; 88: 653– 8 6 Sneyd JR, Simons PJ, Wright B. Use of proton NMR spectroscopy to measure propofol metabolites in the urine of the female Caucasian patient. Xenobiotica 1994; 24: 1021 – 8 7 Allegaert K, Peeters MY, Verbesselt R, et al. Interindividual variability in propofol pharmacokinetics in preterm and term neonates. Br J Anaesth 2007; 99: 864 – 70 8 Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology— drug disposition, action, and therapy in infants and children. N Engl J Med 2003; 349: 1157– 67 9 Allegaert K, de Hoon J, Verbesselt R, et al. Intra- and interindividual variability of glucuronidation of paracetamol during repeated administration of propacetamol in neonates. Acta Paediatr 2005; 94: 1273 – 9 10 Allegaert K, Vanhole C, Vermeersch S, Rayyan M, Verbesselt R, de Hoon J. Both postnatal and postmenstrual age contribute to the interindividual variability in tramadol glucuronidation in neonates. Early Hum Dev 2008; 84: 325 – 30 11 Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH. Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. Br J Anaesth 2004; 92: 208 – 17 12 Allegaert K, Tibboel D, Naulaers G, et al. Systematic evaluation of pain in neonates: effect on the number of intravenous analgesics prescribed. Eur J Clin Pharmacol 2003; 59: 87 –90 13 Favetta P, Guitton J, Degoute CS, Van Daele L, Boulieu R. High-performance liquid chromatographic assay to detect hydroxylate and conjugate metabolites of propofol in human urine. J Chromatogr B Biomed Sci Appl 2000; 742: 25 – 35 14 Vree TB, Lagerwerf AJ, Bleeker CP, de Grood PM. Direct highperformance liquid chromatography determination of propofol and its metabolite quinol with their glucuronide conjugates and preliminary pharmacokinetics in plasma and urine of man. J Chromatogr Biomed Sci Appl 1999; 721: 217 – 28
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glucuronidation capacity, propofol undergoes hydroxylation to 1- and 4-quinol metabolites. On the basis of the current observations on in vivo urinary propofol metabolism, that hydroxylation (likely CYP2B6 dependent) is already present in neonates, which confirms a recent in vitro study on CYP2B6 activity in hepatic and renal microsomal fractions in neonates.16 17 The current data hereby support a cautious use of propofol in neonates since the previously described overall reduced propofol elimination clearance in neonates has been explained by maturational differences in metabolic capacity and by extensive interindividual variability in propofol metabolism in neonates.7 The extensive interindividual variability in propofol biotransformation in neonates could not be explained by the covariates (PMA, PNA, and cardiopathy) evaluated in this study. Phenotypic variation in drug metabolism depends on constitutional, genetic, and environmental factors, but in early life, mainly reflects isoenzyme-specific ontogeny.8 Besides age, covariates such as genetic polymorphisms or disease characteristics may be involved in propofol metabolism. Propofol hydroxylation is mainly mediated by CYP2B6. This isoenzyme displays genetic polymorphisms and can contribute to interindividual variability of drug metabolism in neonates.17 Liver blood flow is another significant covariate of propofol clearance during continuous administration in critically ill adults,5 but data on the agedependent hepatic blood flow in neonates are limited.18 19 The impact of various covariates (age, disease characteristics, and polymorphisms) on interindividual variability in propofol metabolism in neonates remains to be established. Finally, it was recently documented that tubular reabsorption of propofol and its metabolites by the kidney is a major contributor to elimination during continuous administration of propofol in adults that results in propofol metabolites in urine up to 60 h after administration.20 It is therefore striking that in the i.v. bolus model evaluated, the median recovery of propofol metabolites in the first 24 h urine collection is similar in neonates and adults. This might be explained by the limited renal tubular reabsorption in early life compared with adulthood, resulting in renal elimination after glomerular filtration instead of tubular reabsorption, compensating for the limited metabolic capacity in early life.8 20 In conclusion, propofol metabolism in neonates differs profoundly from adults. The current observations are in line with the extensive interindividual variability in propofol metabolic clearance described in early life. On the basis of the extensive variability in early life, this drug should be used cautiously in neonates since accumulation is more likely to occur. The present findings reflect the age-dependent limited glucuronidation capacity while CYP2B6-mediated propofol hydroxylation already contributes to propofol metabolism in neonates. Covariates of the extensive interindividual variability in propofol metabolites in early life were not evident.
Propofol metabolism in early life
15 Simons PJ, Cockshott ID, Douglas EJ, Gordon EA, Hopkins KJ, Rowland M. Disposition in male volunteers of a subanaesthetic intravenous dose of an oil in water emulsion of 14C-propofol. Xenobiotica 1988; 18: 429 – 40 16 Oda Y, Hamaoka N, Hiroi T, et al. Involvement of human liver cytochrome P4502B6 in the metabolism of propofol. Br J Clin Pharmacol 2001; 51: 281 – 5 17 Aleksa K, Matsell D, Krausz K, Gelboin H, Ito S, Koren G. Cytochrome P450 3A and 2B6 in the developing kidney: implications for ifosfamide nephrotoxicity. Pediatr Nephrol 2005; 20: 872–85
18 Allegaert K, Van den Anker JN, de Hoon JN, et al. Covariates of tramadol disposition in the first months of life. Br J Anaesth 2008; 100: 525 – 32 19 Peeters MY, Aarts LP, Boom FA, et al. Pilot study on the influence of liver blood flow and cardiac output on the clearance of propofol in critically ill patients. Eur J Clin Pharmacol 2008; 64: 329 – 34 20 Bleeker C, Vree T, Lagerwerf A, Willems-van Bree E. Recovery and long-term renal excretion of propofol, its glucuronide, and two di-isopropylquinol glucuronides after propofol infusion during surgery. Br J Anaesth 2008; 101: 207 – 12
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