Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen

Introduction: Acetaminophen (paracetamol) is mainly metabolized via glucuronidation and sulphation, while the minor pathway through cytochrome P450 (CYP) 2E1 is held responsible for hepatotoxicity. In obese patients, CYP2E1 activity is reported to be induced, thereby potentially worsening the safety profile of acetaminophen. The aim of this study was to determine the pharmacokinetics of acetaminophen and its metabolites (glucuronide, sulphate, cysteine and mercapturate) in morbidly obese and non-obese patients. Methods: Twenty morbidly obese patients (with a median total body weight [TBW] of 140.1 kg [range 106–193.1 kg] and body mass index [BMI] of 45.1 kg/m2 [40–55.2 kg/m2]) and eight non-obese patients (with a TBW of 69.4 kg [53.4–91.7] and BMI of 21.8 kg/m2 [19.4–27.4]) received 2 g of intravenous acetaminophen. Fifteen blood samples were collected per patient. Population pharmacokinetic modelling was performed using NONMEM. Results: In morbidly obese patients, the median area under the plasma concentration–time curve from 0 to 8 h (AUC0–8h) of acetaminophen was significantly smaller (P = 0.009), while the AUC0–8h ratios of the glucuronide, sulphate and cysteine metabolites to acetaminophen were significantly higher (P = 0.043, 0.004 and 0.010, respectively). In the model, acetaminophen CYP2E1-mediated clearance (cysteine and mercapturate) increased with lean body weight [LBW] (population mean [relative standard error] 0.0185 L/min [15 %], P < 0.01). Moreover, accelerated formation of the cysteine and mercapturate metabolites was found with increasing LBW (P < 0.001). Glucuronidation clearance (0.219 L/min [5 %]) and sulphation clearance (0.0646 L/min [6 %]) also increased with LBW (P < 0.001). Conclusion: Obesity leads to lower acetaminophen concentrations and earlier and higher peak concentrations of acetaminophen cysteine and mercapturate. While a higher dose may be anticipated to achieve adequate acetaminophen concentrations, the increased CYP2E1-mediated pathway may preclude this dose adjustment

The allometric exponent for scaling clearance varies with age: A study on seven propofol datasets ranging from preterm neonates to adults

Aim For scaling clearance between adults and children, allometric scaling with a fixed exponent of 0.75 is often applied. In this analysis, we performed a systematic study on the allometric exponent for scaling propofol clearance between two subpopulations selected from neonates, infants, toddlers, children, adolescents and adults. Methods Seven propofol studies were included in the analysis (neonates, infants, toddlers, children, adolescents, adults1 and adults2). In a systematic manner, two out of the six study populations were selected resulting in 15 combined datasets. In addition, the data of the seven studies were regrouped into five age groups (FDA Guidance 1998), from which four combined datasets were prepared consisting of one paediatric age group and the adult group. In each of these 19 combined datasets, the allometric scaling exponent for clearance was estimated using population pharmacokinetic modelling (nonmem 7.2). Results The allometric exponent for propofol clearance varied between 1.11 and 2.01 in cases where the neonate dataset was included. When two paediatric datasets were analyzed, the exponent varied between 0.2 and 2.01, while it varied between 0.56 and 0.81 when the adult population and a paediatric dataset except for neonates were selected. Scaling from adults to adolescents, children, infants and neonates resulted in exponents of 0.74, 0.70, 0.60 and 1.11 respectively. Conclusions For scaling clearance, allometric scaling may be of value for scaling between adults and adolescents or children, while it can neither be used for neonates nor for two paediatric populations. For scaling to neonates an exponent between 1 and 2 was identified