Effect of Short-Term Fasting on Systemic Cytochrome P450-Mediated Drug Metabolism in Healthy Subjects: A Randomized, Controlled, Crossover Study Using a Cocktail Approach

Background and Objective: Short-term fasting can alter drug exposure but it is unknown whether this is an effect of altered oral bioavailability and/or systemic clearance. Therefore, the aim of our study was to assess the effect of short-term fasting on oral bioavailability and systemic clearance of different drugs. Methods: In a randomized, controlled, crossover trial, 12 healthy subjects received a single administration of a cytochrome P450 (CYP) probe cocktail, consisting of caffeine (CYP1A2), metoprolol (CYP2D6), midazo

The effects of fasting on drug metabolism

Introduction: There is considerable variability in the rates and extent of drug metabolism between patients due to physiological, genetic, pharmacologic, environmental and nutritional factors such as fasting. This variability in drug metabolism may result in treatment failure or, conversely, in increased side effects or toxicity. Preclinical studies have shown that fasting alters drug metabolism by modulating the activity of drug metabolizing enzymes involved. However, until recently little was known about the effects of fasting on drug metabolism in humans. Areas covered: This review describes the effects of fasting on drug metabolism based on both preclinical studies and studies performed in humans. Expert opinion: A better understanding of the effects of fasting may improve the efficacy and safety of pharmacotherapy for individual patients. Fasting contributes to variability in human drug metabolism by differentially affecting drug metabolizing enzymes. Although the effects of fasting on drug metabolism appear to be small (between 10-20%), fasting may be relevant for drugs with a small therapeutic range and/or in combination with other factors that contribute to variability in drug metabolism such as physiological, genetic or pharmacological factors. Therefore, additional research on this topic is warranted

Nutritional Status Differentially Alters Cytochrome P450 3A4 (CYP3A4) and Uridine 5′-Diphospho-Glucuronosyltransferase (UGT) Mediated Drug Metabolism: Effect of Short-Term Fasting and High Fat Diet on Midazolam Metabolism

Background and Objectives: Previous studies have shown that nutritional status can alter drug metabolism which may result in treatment failure or untoward side effects. This study assesses the effect of two nutritional conditions, short-term fasting, and a short-term high fat diet (HFD) on cytochrome P450 3A4 (CYP3A4) and uridine 5′-diphospho-glucuronosyltransferase (UGT) mediated drug metabolism by studying the pharmacokinetics of midazolam and its main metabolites. Methods: In a randomized-controlled cross-over trial, nine healthy subjects received a single intravenous administration of 0.015 mg/kg midazolam after: (1) an overnight fast (control); (2) 36 h of fasting; and (3) an overnight fast after 3 days of a HFD consisting of 500 ml of cream supplemented to their regular diet. Pharmacokinetic parameters were analyzed simultaneously using non-linear mixed-effects modeling. Results: Short-term fasting increased CYP3A4-mediated midazolam clearance by 12% (p < 0.01) and decreased UGT-mediated metabolism apparent 1-OH-midazolam clearance by 13% (p < 0.01) by decreasing the ratio of clearance and the fraction metabolite formed (ΔCL1-OH-MDZ/f1-OH-MDZ). Furthermore, short-term fasting decreased apparent clearance of 1-OH-midazolam-O-glucuronide (CL1-OH-MDZ-glucuronide/(f1-OH-MDZ-glucuronide × f1-OH-MDZ)) by 20% (p < 0.01). The HFD did not affect systemic clearance of midazolam or metabolites. Conclusions: Short-term fasting differentially alters midazolam metabolism by increasing CYP3A4-mediated metabolism but by decreasing UGT-mediated metabolism. In contrast, a short-term HFD did not affect systemic clearance of midazolam

Short-Term Fasting Alters Pharmacokinetics of Cytochrome P450 Probe Drugs: Does Protein Binding Play a Role?

Short-term fasting differentially alters cytochrome P450 (CYP) mediated drug metabolism. This has been established by using CYP-enzyme selective probe drugs. However, the observed effects of fasting on the pharmacokinetics of these probe drugs may also include the effects of altered plasma protein binding of these drugs. Therefore, we studied the effect of short-term fasting on protein binding of five commonly used probe drugs [caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19) and S-warfarin (CYP2C9)]. The free and total plasma concentrations of the five probe drugs were analyzed by LC-MS/MS in samples retrieved in a cross-over study in which nine healthy subjects received an intravenous administration of the cocktail after an overnight fast (control) and after 36 h of fasting. Short-term fasting increased plasma free fatty acid concentrations from 0.48 mmol/L (control) to 1.29 mmol/L (36 h fasting) (p = 0.012). Short-term fasting did not alter the free fractions of caffeine, metoprolol and omeprazole compared to the control intervention (p > 0.05). Power to detect a difference for midazolam and S-warfarin was low since the majority of free concentrations were below the limit of quantification. This study demonstrates that short-term fasting does not alter protein binding of the probe drugs caffeine, metoprolol and omeprazol

Short-Term High-Fat Diet Alters Acetaminophen Metabolism in Healthy Individuals

BACKGROUND: Acetaminophen is metabolized through a nontoxic sulfation and glucuronidation pathway and toxic oxidation pathway (via CYP2E1 and CYP1A2). A short-term high-fat diet induces alterations in the steatotic liver and may alter hepatic drug enzyme activity. In the case of acetaminophen, these alterations may result in an increased risk of hepatotoxicity. Therefore, this study was conducted to assess the effect of a 3-day hypercaloric high-fat diet on the plasma levels of acetaminophen metabolites. METHODS: Nine healthy subjects participated in this randomized, crossover intervention study. The subjects consumed a regular diet or a regular diet supplemented with 500 mL of cream (1700 kcal) for 3 days and then fasted overnight. After ingesting 1000-mg acetaminophen, the plasma concentration of acetaminophen (APAP) and its metabolites [acetaminophen glucuronide, acetaminophen sulfate, 3-cysteinyl-acetaminophen, and 3-(N-acetyl-L-cystein-S-yl)-acetaminophen, and 3-methoxy-acetaminophen] were measured. RESULTS: The 3-day high-fat diet increased the extrapolated area under the concentration-time curve from 0 to infinity (area under the curve 0-inf ) of APAP-Cys by approximately 20% ( P = 0.02) and that from 0 to 8 hours (area under the curve 0-8 ) of APAP-Cys-NAC by approximately 39% ( P = 0.01). The 3-day high-fat diet did not alter the pharmacokinetic parameters of the parent compound acetaminophen and other metabolites. CONCLUSIONS: A short-term, hypercaloric, high-fat diet increases the plasma levels of the APAP metabolites formed by the oxidation pathway, which may increase the risk of hepatotoxicity

Sorafenib for Patients with Hepatocellular Carcinoma and Child-Pugh B Liver Cirrhosis: Lessons Learned from a Terminated Study

Lessons Learned: Recruitment of patients with advanced hepatocellular carcinoma and Child-Pugh B for sorafenib treatment and additional pharmacokinetic studies is challenging. Patients with Child-Pugh B liver cirrhosis have high rates of cirrhosis-related adverse events. Background: Few data are available on the pharmacokinetics (PK) of sorafenib in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh B liver cirrhosis. This study aimed to explore the sorafenib PK and its relationship with efficacy and toxicity in these patients. Methods: Patients with advanced HCC and Child-Pugh B7-8 liver function were prospectively recruited at a tertiary center. Adverse events (AEs), progression-free survival (PFS), and overall survival (OS) were recorded. Patients received a starting dose of 200 b.i.d. with toxicity-adjusted dose escalation to a target dose of 400 mg b.i.d. with PK sampling at fixed time points. Results: Between May 2014 and March 2017, 12 patients were screened, of whom 7 progressed to a terminal stage during the screening (n = 6) or shortly after recruitment (n = 1). The five included patients had median PFS of 3.8 months (range, 1.7–10.8) and OS of 7.4 months (range, 1.7–25.8). Three patients had severe AEs and one patient had a partial response with an OS of 25.8 months. In 2017, the trial was aborted for lack of accrual. Conclusion: Because of low accrual, no conclusion can be drawn on the sorafenib PK in patients with advanced HCC and Child-Pugh B liver cirrhosis. The poor survival and frequent cirrhosis-related AEs suggest limited benefit for most of these patients

Quantitative Method for Simultaneous Analysis of Acetaminophen and 6 Metabolites

Hepatotoxicity after ingestion of high-dose acetaminophen [N-acetyl-para-aminophenol (APAP)] is caused by the metabolites of the drug. To gain more insight into factors influencing susceptibility to APAP hepatotoxicity, quantification of APAP and metabolites is important. A few methods have been developed to simultaneously quantify APAP and its most important metabolites. However, these methods require a comprehensive sample preparation and long run times. The aim of this study was to develop and validate a simplified, but sensitive method for the simultaneous quantification of acetaminophen, the main metabolites acetaminophen glucuronide and acetaminophen sulfate, and 4 Cytochrome P450-mediated metabolites by using liquid chromatography with mass spectrometric (LC-MS) detection. The method was developed and validated for the human plasma, and it entailed a single method for sample preparation, enabling quick processing of the samples followed by an LC-MS method with a chromatographic run time of 9 minutes. The method was validated for selectivity, linearity, accuracy, imprecision, dilution integrity, recovery, process efficiency, ionization efficiency, and carryover effect. The method showed good selectivity without matrix interferences. For all analytes, the mean process efficiency was >86%, and the mean ionization efficiency was >94%. Furthermore, the accuracy was between 90.3% and 112% for all analytes, and the within- and between-run imprecision were <20% for the lower limit of quantification and <14.3% for the middle level and upper limit of quantification. The method presented here enables the simultaneous quantification of APAP and 6 of its metabolites. It is less time consuming than previously reported methods because it requires only a single and simple method for the sample preparation followed by an LC-MS method with a short run time. Therefore, this analytical method provides a useful method for both clinical and research purpose

Effect of Short-Term Fasting on Systemic Cytochrome P450-Mediated Drug Metabolism in Healthy Subjects: A Randomized, Controlled, Crossover Study Using a Cocktail Approach

Short-term fasting can alter drug exposure but it is unknown whether this is an effect of altered oral bioavailability and/or systemic clearance. Therefore, the aim of our study was to assess the effect of short-term fasting on oral bioavailability and systemic clearance of different drugs. In a randomized, controlled, crossover trial, 12 healthy subjects received a single administration of a cytochrome P450 (CYP) probe cocktail, consisting of caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19) and warfarin (CYP2C9), on four occasions: an oral (1) and intravenous (2) administration after an overnight fast (control) and an oral (3) and intravenous (4) administration after 36 h of fasting. Pharmacokinetic parameters of the probe drugs were analyzed using the nonlinear mixed-effects modeling software NONMEM. Short-term fasting increased systemic caffeine clearance by 17% (p = 0.04) and metoprolol clearance by 13% (p <0.01), whereas S-warfarin clearance decreased by 19% (p <0.01). Fasting did not affect bioavailability. The study demonstrates that short-term fasting alters CYP-mediated drug metabolism in a non-uniform pattern without affecting oral bioavailabilit