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.

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.

Differential effects of a 40-hour fast and bile acid supplementation on human GLP-1 and FGF19 responses.

Bile acids, glucagon-like peptide-1 (GLP-1), and fibroblast growth factor 19 (FGF19) play an important role in postprandial metabolism. In this study, we investigated the postprandial bile acid response in plasma and its relation to insulin, GLP-1, and FGF19. First, we investigated the postprandial response to 40-h fast. Then we administered glycine-conjugated deoxycholic acid (gDCA) with the meal. We performed two separate observational randomized crossover studies on healthy, lean men. In experiment 1: we tested 4-h mixed meal after an overnight fast and a 40-h fast. In experiment 2, we tested a 4-h mixed meal test with and without gDCA supplementation. Both studies measured postprandial glucose, insulin, bile acids, GLP-1, and FGF19. In experiment 1, 40 h of fasting induced insulin resistance and increased postprandial GLP-1 and FGF19 concentrations. After an overnight fast, we observed strong correlations between postprandial insulin and gDCA levels at specific time points. In experiment 2, administration of gDCA increased GLP-1 levels and lowered late postprandial glucose without effect on FGF19. Energy expenditure was not affected by gDCA administration. Unexpectedly, 40 h of fasting increased both GLP-1 and FGF19, where the former appeared bile acid independent and the latter bile acid dependent. Second, a single dose of gDCA increased postprandial GLP-1. Therefore, our data add complexity to the physiological regulation of the enterokines GLP-1 and FGF19 by bile acids.

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?

BACKGROUND AND OBJECTIVES: 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)]. METHODS: 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. RESULTS: 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. CONCLUSIONS: This study demonstrates that short-term fasting does not alter protein binding of the probe drugs caffeine, metoprolol and omeprazole.

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), 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. RESULTS: 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. CONCLUSION: The study demonstrates that short-term fasting alters CYP-mediated drug metabolism in a non-uniform pattern without affecting oral bioavailability.

Quantitative Method for Simultaneous Analysis of Acetaminophen and 6 Metabolites.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 purposes.

Quantitative Method for Simultaneous Analysis of a 5-Probe Cocktail for Cytochrome P450 Enzymes.

BACKGROUND: The metabolic activity of P450 enzymes in vivo can be determined using selective probe drugs. The simultaneous administration of multiple CYP-specific probe drugs is commonly known as the "cocktail approach." Disadvantages of a cocktail are large volumes of samples required for analysis and time-consuming analyses. The aim of this study was to develop and validate a simplified but sensitive method for the simultaneous quantification of 5 probe drugs [caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19), and S-warfarin (CYP2C9)] in a previously validated cocktail using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. METHODS: The method entailed a single method for sample preparation that enables quick processing of the samples containing all 5 probe drugs in a small volume of blood (≥10 µL) followed by a chiral and nonchiral LC-MS/MS method. The method was validated for selectivity, specificity, resolution of racemic warfarin, linearity, accuracy, imprecision, recovery, process efficiency, ionization efficiency, and carryover effect. RESULTS: The method showed good selectivity without matrix interferences and differentiated S- and R-warfarin enantiomers with adequate resolution (Rs = 1.55). For all analytes, the mean process efficiency was >95%, and the mean ionization efficiency was >97%. Furthermore, the accuracy was between 94.9% and 108% for all analytes, and the within- and between-run imprecision were <11.7% for the lower limit of quantification and <12.6% for the middle level and upper limit of quantification. CONCLUSIONS: The method presented here enables the simultaneous quantification of the 5 probes in a very small blood volume (≥10 µL). Furthermore, it is less time consuming than previously reported methods because it requires only 1 simple method for sample preparation followed by a nonchiral and chiral LC-MS/MS method that can be performed sequentially.

A short-term high fat diet increases exposure to midazolam and omeprazole in healthy subjects.

OBJECTIVES: Knowledge of factors contributing to variation in drug metabolism is of vital importance to optimize drug treatment. This study assesses the effects of a short-term hypercaloric high fat diet on metabolism of five oral drugs, which are each specific for a single P450 isoform: midazolam (CYP3A4), omeprazole (CYP2C19), metoprolol (CYP2D6), S-warfarin (CYP2C9) and caffeine (CYP1A2). METHODS: In 9 healthy volunteers, pharmacokinetics of the five drugs were assessed after an overnight fast at two separate occasions: after a regular diet and after 3 days of a hypercaloric high fat diet (i.e. regular diet supplemented with 500 mL cream [1715 kcal, 35% fat]). Pharmacokinetic parameters (mean [SEM]) were estimated by non-compartmental analysis. RESULTS: The high fat diet increased exposure to midazolam by 19% from 24.7 (2.6) to 29.5 (3.6) ng ml-1h-1 (p=0.04) and exposure to omeprazole by 31% from 726 (104) to 951 (168) ng ml-1h-1 (p=0.05). Exposure to metoprolol, caffeine and S-warfarin was not affected by the high fat diet. CONCLUSION: A short-term hypercaloric high fat diet increases exposure to midazolam and omeprazole, possibly reflecting modulation of CYP3A4 and CYP2C19.

Management of Functional Constipation in Children: Therapy in Practice.

Functional constipation is a common healthcare problem among children worldwide and accounts for high healthcare usage and costs. Functional constipation is a clinical diagnosis; the evaluation primarily consists of a thorough medical history and a complete physical examination. Additional investigations are not necessary in most cases. Treatment consists of non-pharmacological and pharmacological interventions. Non-pharmacological interventions involve education and demystification, toilet training (with a reward system), and a defecation diary. Pharmacological treatment comprises three steps: disimpaction, maintenance treatment, and weaning. The treatment of first choice is oral laxatives, preferably polyethylene glycol. When this is insufficient, other therapeutic agents are available. This review discusses the evaluation and management of functional constipation in the pediatric population and provides a summary of drug treatment options.

Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial.

BACKGROUND: The peritoneum is the second most common site of recurrence in colorectal cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult. Patients eventually presenting with clinically apparent PC have a poor prognosis. Median survival is only about five months if untreated and the benefit of palliative systemic chemotherapy is limited. Only a quarter of patients are eligible for curative treatment, consisting of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC). However, the effectiveness depends highly on the extent of disease and the treatment is associated with a considerable complication rate. These clinical problems underline the need for effective adjuvant therapy in high-risk patients to minimize the risk of outgrowth of peritoneal micro metastases. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) seems to be suitable for this purpose. Without the need for cytoreductive surgery, adjuvant HIPEC can be performed with a low complication rate and short hospital stay. METHODS/DESIGN: The aim of this study is to determine the effectiveness of adjuvant HIPEC in preventing the development of PC in patients with colon cancer at high risk of peritoneal recurrence. This study will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible for inclusion are patients who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. After resection of the primary tumour, 176 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously or shortly after the primary resection. Oxaliplatin will be used as chemotherapeutic agent, for 30 min at 42-43 °C. Just before HIPEC, 5-fluorouracil and leucovorin will be administered intravenously. Primary endpoint is peritoneal disease-free survival at 18 months. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA. DISCUSSION: Adjuvant HIPEC is assumed to reduce the expected 25 % absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10 %. This reduction is likely to translate into a prolonged overall survival. TRIAL REGISTRATION NUMBER: NCT02231086 (Clinicaltrials.gov).

Short-term fasting alters cytochrome P450-mediated drug metabolism in humans.

Experimental studies indicate that short-term fasting alters drug metabolism. However, the effects of short-term fasting on drug metabolism in humans need further investigation. Therefore, the aim of this study was to evaluate the effects of short-term fasting (36 h) on P450-mediated drug metabolism. In a randomized crossover study design, nine healthy subjects ingested a cocktail consisting of five P450-specific probe drugs [caffeine (CYP1A2), S-warfarin (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6), and midazolam (CYP3A4)] on two occasions (control study after an overnight fast and after 36 h of fasting). Blood samples were drawn for pharmacokinetic analysis using nonlinear mixed effects modeling. In addition, we studied in Wistar rats the effects of short-term fasting on hepatic mRNA expression of P450 isoforms corresponding with the five studied P450 enzymes in humans. In the healthy subjects, short-term fasting increased oral caffeine clearance by 20% (P = 0.03) and decreased oral S-warfarin clearance by 25% (P < 0.001). In rats, short-term fasting increased mRNA expression of the orthologs of human CYP1A2, CYP2C19, CYP2D6, and CYP3A4 (P < 0.05), and decreased the mRNA expression of the ortholog of CYP2C9 (P < 0.001) compared with the postabsorptive state. These results demonstrate that short-term fasting alters cytochrome P450-mediated drug metabolism in a nonuniform pattern. Therefore, short-term fasting is another factor affecting cytochrome P450-mediated drug metabolism in humans.

Effect of extended-release naltrexone on striatal dopamine transporter availability, depression and anhedonia in heroin-dependent patients.

RATIONALE: Extended-release naltrexone (XRNT), an opioid receptor antagonist, is successfully used in the treatment of opioid dependence. However, naltrexone treatment of opioid-dependent patients may reduce striatal dopamine transporter (DAT) availability and cause depression and anhedonia. OBJECTIVES: The aim of this study is to investigate changes in striatal DAT availability and symptoms of depression (Beck Depression Inventory (BDI)) and anhedonia (Snaith Hamilton Pleasure Scale (SHAPS)) before and during XRNT treatment. METHODS: At baseline, ten detoxified heroin-dependent patients and 11 matched healthy controls underwent [(123)I]FP-CIT single photon emission computed tomography (SPECT) imaging to assess striatal DAT binding. Patients underwent a second SPECT scan 2 weeks after an intramuscular injection with XRNT. RESULTS: At baseline, the mean binding potential (BPND) in the putamen was at a trend level lower and the mean BDI score was significantly higher in heroin patients (n = 10) than in controls (n = 11) (3.45 ± 0.88 vs. 3.80 ± 0.61, p = 0.067, d = -0.48 and 12.75 ± 7.40 vs. 5.20 ± 4.83, p = 0.019, d = 1.24, respectively). Post hoc analyses in subgroups with negative urine analyses for opioids and cocaine showed significantly lower baseline putamen BPND in heroin patients (n = 8) than controls (n = 10) (3.19 ± 0.43 vs. 3.80 ± 0.64, p = 0.049, d = -1.03). XRNT treatment in heroin patients was not significantly associated with changes in striatal DAT availability (p = 0.348, d = 0.48), but the mean BDI score after XRNT treatment was significantly lower than before treatment (7.75 ± 7.21 vs. 12.75 ± 7.40, p = 0.004, d = -0.68). CONCLUSIONS: The results of this study suggest that XRNT treatment does not reduce striatal DAT availability and has no significant effect on anhedonia, but is associated with a significant reduction of depressive symptoms.

The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users.

Cytochrome P450 2D6 (CYP2D6) plays an important role in the formation of endoxifen, the active metabolite of tamoxifen. In this study the association between the most prevalent CYP2D6 null-allele in Caucasians (CYP2D6*4) and breast cancer mortality was examined among all incident users of tamoxifen in a population-based cohort study. Breast cancer mortality was significantly increased in patients with the * 4/*4 genotype (HR = 4.1, CI 95% 1.1-15.9, P = 0.041) compared to wild type patients. The breast cancer mortality increased with a hazard ratio of 2.0 (CI 95% 1.1-3.4, P = 0.015) with each additional variant allele. No increased risk of all-cause mortality or all-cancer mortality was found in tamoxifen users carrying a CYP2D6*4 allele. The risk of breast cancer mortality is increased in tamoxifen users with decreased CYP2D6 activity, consistent with the model in which endoxifen formation is dependent on CYP2D6 activity.