Yi Zheng1, Pan-Pan Ye2, Yue Zhou1, Su-Ying Wu3, Xi-Ting Liu1, Bin Du1, Bo-Hao Tang1, Min Kan1, Ai-Qing Nie1, Rui Yin1, Meng Wang1, Guo-Xiang Hao1, Lin-Lin Song2, Xin-Mei Yang2, Xin Huang2, Le-Qun Su2, Wen-Qi Wang2, John van den Anker4,5,6, Wei Zhao1,2. 1. Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People's Republic of China. 2. Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, 250014, People's Republic of China. 3. Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China. 4. Division of Clinical Pharmacology, Children's National Hospital, Washington, DC, USA. 5. Departments of Pediatrics, Pharmacology & Physiology, Genomics & Precision Medicine, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA. 6. Department of Paediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, University of Basel, Basel, Switzerland.
Abstract
PURPOSE: Inflammation has a significant impact on CYP3A activity. We hypothesized that this effect might be age dependent. Our objective was to conduct a population pharmacokinetic study of midazolam in mice at different developmental stages with varying degrees of inflammation to verify our hypothesis. METHODS: Different doses (2 and 5 mg/kg) of lipopolysaccharide (LPS) were used to induce different degrees of systemic inflammation in Swiss mice (postnatal age 9-42 days, n = 220). The CYP3A substrate midazolam was selected as the pharmacological probe to study CYP3A activity. Postnatal age, current body weight, serum amyloid A protein 1 (SAA1) levels and LPS doses were collected as covariates to perform a population pharmacokinetic analysis using NONMEM 7.2. RESULTS: A population pharmacokinetic model of midazolam in juvenile and adult mice was established. Postnatal age and current body weight were the most significant and positive covariates for clearance and volume of distribution. LPS dosage was the most significant and negative covariate for clearance. LPS dosage can significantly reduce the clearance of midazolam by 21.8% and 38.7% with 2 mg/kg and 5 mg/kg, respectively. Moreover, the magnitude of the reduction was higher in mice with advancing postnatal age. CONCLUSION: Both inflammation and ontogeny have an essential role in CYP3A activity in mice. The effect of LPS-induced systemic inflammation on midazolam clearance in mice is dependent on postnatal age.
PURPOSE: Inflammation has a significant impact on CYP3A activity. We hypothesized that this effect might be age dependent. Our objective was to conduct a population pharmacokinetic study of midazolam in mice at different developmental stages with varying degrees of inflammation to verify our hypothesis. METHODS: Different doses (2 and 5 mg/kg) of lipopolysaccharide (LPS) were used to induce different degrees of systemic inflammation in Swiss mice (postnatal age 9-42 days, n = 220). The CYP3A substrate midazolam was selected as the pharmacological probe to study CYP3A activity. Postnatal age, current body weight, serum amyloid A protein 1 (SAA1) levels and LPS doses were collected as covariates to perform a population pharmacokinetic analysis using NONMEM 7.2. RESULTS: A population pharmacokinetic model of midazolam in juvenile and adult mice was established. Postnatal age and current body weight were the most significant and positive covariates for clearance and volume of distribution. LPS dosage was the most significant and negative covariate for clearance. LPS dosage can significantly reduce the clearance of midazolam by 21.8% and 38.7% with 2 mg/kg and 5 mg/kg, respectively. Moreover, the magnitude of the reduction was higher in mice with advancing postnatal age. CONCLUSION: Both inflammation and ontogeny have an essential role in CYP3A activity in mice. The effect of LPS-induced systemic inflammation on midazolam clearance in mice is dependent on postnatal age.
Authors: Roosmarijn F W De Cock; Chiara Piana; Elke H J Krekels; Meindert Danhof; Karel Allegaert; Catherijne A J Knibbe Journal: Eur J Clin Pharmacol Date: 2010-03-26 Impact factor: 2.953
Authors: Linda G Franken; Anniek D Masman; Brenda C M de Winter; Frans P M Baar; Dick Tibboel; Teun van Gelder; Birgit C P Koch; Ron A A Mathot Journal: Br J Clin Pharmacol Date: 2017-03-31 Impact factor: 4.335