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Why dose adjust systemic exposure when looking for associations with adverse events in tacrolimus-treated transplant recipients? Keywords: adverse drug reactions; drug metabolism; other; pharmacokinetics; transplantation EN adverse drug reactions drug metabolism other pharmacokinetics transplantation 2535 2535 1 11/28/20 20201201 NES 201201 The article by Campagne et al1 highlights a timely issue in modern immunosuppressive therapy of transplanted patients; what is the impact of tacrolimus (Tac) exposure on extrarenal adverse effects? Adverse drug reactions, drug metabolism, other, pharmacokinetics, transplantation. [Extracted from the article]

We appreciate the input of Drs Yildiz and Yildiz.[1] They suggest an addition to our review on the bioavailability of immunosuppressive drugs after bariatric surgery,[2] specifically in relation to transplantation surgery. Our general recommendation would therefore be to use standard TDM procedure in patients transplanted after bariatric surgery and to intensify TDM in case of bariatric surgery in transplanted patients. [Extracted from the article]

Importance: Roux-en-Y gastric bypass (RYGB) is associated with reduced cardiovascular (CV) risk factors, morbidity, and mortality. Whether these effects are specifically induced by the surgical procedure or the weight loss is unclear., Objective: To compare 6-week changes in CV risk factors in patients with obesity undergoing matching caloric restriction and weight loss by RYGB or a very low-energy diet (VLED)., Design, Setting, and Participants: This nonrandomized controlled study (Impact of Body Weight, Low Calorie Diet, and Gastric Bypass on Drug Bioavailability, Cardiovascular Risk Factors, and Metabolic Biomarkers [COCKTAIL]) was conducted at a tertiary care obesity center in Norway. Participants were individuals with severe obesity preparing for RYGB or a VLED. Recruitment began February 26, 2015; the first patient visit was on March 18, 2015, and the last patient visit (9-week follow-up) was on August 9, 2017. Data were analyzed from April 30, 2021, through June 29, 2023., Interventions: VLED alone for 6 weeks or VLED for 6 weeks after RYGB; both interventions were preceded by 3-week LED., Main Outcomes and Measures: Between-group comparisons of 6-week changes in CV risk factors., Results: Among 78 patients included in the analyses, the mean (SD) age was 47.5 (9.7) years; 51 (65%) were women, and 27 (35%) were men. Except for a slightly higher mean (SD) body mass index of 44.5 (6.2) in the RYGB group (n = 41) vs 41.9 (5.4) in the VLED group (n = 37), baseline demographic and clinical characteristics were similar between groups. Major atherogenic blood lipids (low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein[a]) were reduced after RYGB in comparison with VLED despite a similar fat mass loss. Mean between-group differences were -17.7 mg/dL (95% CI, -27.9 to -7.5), -17.4 mg/dL (95% CI, -29.8 to -5.0) mg/dL, -9.94 mg/dL (95% CI, -15.75 to -4.14), and geometric mean ratio was 0.55 U/L (95% CI, 0.42 to 0.72), respectively. Changes in glycemic control and blood pressure were similar between groups., Conclusions and Relevance: This study found that clinically meaningful reductions in major atherogenic blood lipids were demonstrated after RYGB, indicating that RYGB may reduce CV risk independent of weight loss., Trial Registration: ClinicalTrials.gov Identifier: NCT02386917.

The liver and small intestine restrict oral bioavailability of drugs and constitute the main sites of pharmacokinetic drug-drug interactions. Hence, detailed data on hepatic and intestinal activities of drug metabolizing enzymes is important for modeling drug disposition and optimizing pharmacotherapy in different patient populations. The aim of this study was to determine the activities of seven cytochrome P450 (P450) enzymes in paired liver and small intestinal samples from patients with obesity. Biopsies were obtained from 20 patients who underwent Roux-en-Y gastric bypass surgery following a 3-week low-energy diet. Individual hepatic and intestinal microsomes were prepared and specific probe substrates in combined incubations were used for determination of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A activities. The activities of CYP2C8, CYP2C9, CYP2D6, and CYP3A were quantified in both human liver microsomes (HLM) and human intestinal microsomes (HIM), while the activities of CYP1A2, CYP2B6, and CYP2C19 were only quantifiable in HLM. Considerable interindividual variability was present in both HLM (9- to 23-fold) and HIM (5- to 55-fold). The median metabolic HLM/HIM ratios varied from 1.5 for CYP3A to 252 for CYP2C8. The activities of CYP2C9 in paired HLM and HIM were positively correlated ( r = 0.74, P < 0.001), while no interorgan correlations were found for activities of CYP2C8, CYP2D6, and CYP3A ( P > 0.05). Small intestinal CYP3A activities were higher in females compared with males ( P < 0.05). Hepatic CYP2B6 activity correlated negatively with body mass index ( r = -0.72, P < 0.001). These data may be useful for further in vitro-in vivo predictions of drug disposition in patients with obesity. SIGNIFICANCE STATEMENT: Hepatic and intestinal drug metabolism is the key determinant of oral drug bioavailability. In this study, paired liver and jejunum samples were obtained from 20 patients with obesity undergoing gastric bypass surgery following a 3-week low-energy diet. We determined the hepatic and small intestinal activities of clinically important P450 enzymes and provide detailed enzyme kinetic data relevant for predicting in vivo disposition of P450 substrates in this patient population., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Introduction: There is an increasing demand for accurately measured glomerular filtration rate (GFR). Iohexol serum clearance has become a new gold standard, but it is challenging when GFR is low and 24-hour sampling is required for accurate results. The primary aim of this study was to develop an iohexol pharmacokinetic population model for accurate determination of individual GFR using limited sampling for up to 5 hours also when renal function is <40 ml/min., Methods: A nonparametric iohexol population pharmacokinetic model was developed with rich data from 176 patients. In a validation cohort of 43 patients, a model-determined GFR (iohexol clearance) using different limited sampling strategies for up to 5 hours was compared with the strategy currently used in routine care, a log-linear 2-point method. In all, 1526 iohexol concentrations were used, from patients ranging in age from 1 to 82 years and GFR from 14 to 149 ml/min., Results: The clinical 2-point method showed insufficient agreement compared with reference values; 15% of GFR values had an error of greater than ±10% even when sampling for 24 hours when estimating GFR <40 ml/min per 1.73 m 2 (standard procedure). Restricted sampling the first 5 hours with the population model required 4 samples to determine GFR accurately. This strategy showed excellent agreement with the reference; <3% of GFR values had an error greater than ±10 %., Conclusion: Using an iohexol population pharmacokinetic model allows for accurate determination of GFR within 5 hours when applying 4 optimally timed samples, even in patients with GFR <40 ml/min., (© 2019 International Society of Nephrology. Published by Elsevier Inc.)