A short-term high fat diet increases exposure to midazolam and omeprazole in healthy subjects (original) (raw)
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European Journal of Drug Metabolism and Pharmacokinetics
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 0-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 (DCL 1-OH-MDZ /f 1-OH-MDZ). Furthermore, short-term fasting decreased apparent clearance of 1-OH-midazolam-O-glucuronide (CL 1-OH-MDZ-glucuronide /(f 1-OH-MDZ-glucuronide 9 f 1-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.
Clinical Pharmacokinetics
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.
Short-Term Fasting alters Cytochrome P450 mediated Drug Metabolism in Humans
Drug metabolism and disposition: the biological fate of chemicals, 2015
Experimental studies indicate that short-term fasting alters drug metabolism. However, the effects of short-term fasting on drug metabolism in human need further investigation. Therefore, the aim of this study was to evaluate the effects of short-term fasting (36h) on CYP450-mediated drug metabolism. In a randomized cross-over study design, nine healthy subjects ingested a cocktail consisting of five CYP-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 36h of fasting). Blood samples were drawn for pharmacokinetic (PK) analysis using nonlinear mixed effects modeling (NONMEM). In addition, we studied in Wistar rats the effects of short-term fasting on hepatic mRNA expression of CYP-isoforms corresponding with the five studied CYP-enzymes in humans. In the healthy subjects, short-term fasting increased oral caffeine clearance by 20% (p=0.03) a...
European Journal of Nutrition, 2020
Background Cytochrome P450s (CYPs) are a class of hemoproteins involved in drug metabolism. It has been reported that body composition, proportion of dietary macronutrients, fasting and nutritional status can interfere with the activity of drug-metabolizing CYPs. Objectives The present systematic review was conducted to summarize the effect of obesity, weight reduction, macronutrients, fasting and malnutrition on the CYP-mediated drug metabolism. Methods PubMed (Medline), Scopus, Embase and Cochrane Library databases and Google Scholar were searched up to June 2020 to obtain relevant studies. The PRISMA guidelines were employed during all steps. Two reviewers independently extracted the information from the included studies. Studies investigating CYPs activity directly or indirectly through pharmacokinetics of probe drugs, were included. Increase in clearance (CL) or decrease in elimination half-life (t½) and area under the curve (AUC) of probe drugs were considered as increase in CYPs activity. Results A total of 6545 articles were obtained through searching databases among which 69 studies with 126 datasets fully met the inclusion criteria. The results indicated that obesity might decrease the activity of CYP3A4/5, CYP1A2 and CYP2C9 and increase the activity of CYP2E1. The effect of obesity on CYP2D6 is controversial. Also, weight loss increased CYP3A4 activity. Moreover, CYP1A2 activity was decreased by high carbohydrate diet, increased by high protein diet and fasting and unchanged by malnutrition. The activity of CYP2C19 was less susceptible to alterations compared to other CYPs. Conclusion The activity of drug-metabolizing CYPs are altered by body composition, dietary intake and nutritional status. This relationship might contribute to drug toxicity or reduce treatment efficacy and influence cost-effectiveness of medical care.
European Journal of Drug Metabolism and Pharmacokinetics
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.
Pharmacy and Pharmacology Communications
Evaluation of the unbound concentration of an inhibitor (I u) at a target site is the key to predicting in-vivo drug±drug interactions in metabolism, based on in-vitro data. In this study, the in-vivo hepatic extraction ratio (E H) and intrinsic clearance (CL int) of midazolam, a cytochrome P450 (CYP) 3A substrate, in the presence of ketoconazole, a CYP inhibitor, was predicted. The plasma concentration of unbound ketoconazole (I u) in the portal vein or hepatic vein was evaluated in untreated and dexamethasone-pretreated rats. The in-vivo E H of midazolam in the presence and absence of ketoconazole was, 0Á70 and 0Á86 in untreated rats, and 0Á81 and 0Á98 in dexamethasone-pretreated rats, respectively. The in-vivo CL int of midazolam under different conditions was estimated using well-stirred, parallel-tube and dispersion models. The in-vivo E H of ketoconazole alone was approximately 0Á59. The invitro CL int of midazolam was 0Á95 and 3Á44 mL min À1 (mg microsomal protein) À1 in untreated and dexamethasone-pretreated rats, respectively. K i values of ketoconazole, which showed non-competitive inhibition, were 0Á126 and 0Á063 mM in untreated and dexamethasone-pretreated rats, respectively. The predicted in-vivo CL int and E H values of midazolam in the presence of ketoconazole based on in-vitro data using the portal I u as the I u of ketoconazole in the liver were in good agreement with corresponding in-vivo values, determined using parallel-tube and dispersion models. The in-vivo hepatic metabolic clearance of midazolam in the presence of ketoconazole was reasonably predicted from in-vitro data using the portal rather than the hepatic I u , as the I u of ketoconazole in the liver.
Journal of Pharmacy and Pharmacology, 1999
The metabolic clearance of midazolam, a cytochrome P450 (CYP) 3A substrate, by the liver under normal and increased enzyme activity in rats was determined in-vivo and in-vitro to elucidate the reproducibility of the in-vivo hepatic extraction ratio of midazolam from the in-vitro study. The hepatic enzyme activity was modified by pretreating rats with a CYP inducer such as dexamethasone and clotrimazole. The in-vivo hepatic extraction ratio (ERh,obs) of midazolam under a steady-state plasma concentration (approx. 3 nmol mL−1) in untreated (control) rats was 0.864. This value increased to 0.984 in dexamethasone-pretreated rats and to 0.964 in clotrimazole-pretreated rats. The in-vitro hepatic intrinsic clearance (CLint,in-vitro), expressed as mL min−1 (mg microsomal protein)−1, of midazolam was estimated as Vmax (Km)−1 by in-vitro metabolism studies using liver microsomes. The CLint,in-vitro value was converted to the CLint,cal value, expressed as mL min−1 kg−1, by considering the mic...
PloS one, 2016
Hepatic drug metabolism by cytochrome P450 enzymes is altered by the nutritional status of patients. The expression of P450 enzymes is partly regulated by the constitutive androstane receptor (CAR). Fasting regulates the expression of both P450 enzymes and CAR and affects hepatic drug clearance. We hypothesized that the fasting-induced alterations in P450 mediated drug clearance are mediated by CAR. To investigate this we used a drug cocktail validated in humans consisting of five widely prescribed drugs as probes for specific P450 enzymes: caffeine (CYP1A2), metoprolol (CYP2D6), omeprazole (CYP2C19), midazolam (CYP3A4) and s-warfarin (CYP2C9). This cocktail was administered to wild type (WT, C57Bl/6) mice or mice deficient for CAR (CAR-/-) that were either fed ad libitum or fasted for 24 hours. Blood was sampled at predefined intervals and drug concentrations were measured as well as hepatic mRNA expression of homologous/orthologous P450 enzymes (Cyp1a2, Cyp2d22, Cyp3a11, Cyp2c37, ...
The effect of dietary energy and protein deficiency on drug metabolism
European Journal of Clinical Pharmacology, 1990
The influence of a diet deficient in energy or protein on hepatic oxidation (Phase I reactions) and glucuronidation (Phase II reactions) in man has been examined. Nine healthy volunteers were fed an energy deficient diet (daily energy intake 4.3 M J; daily protein intake 0.94 g/kg) and a protein deficient diet (daily energy intake 11.4 MJ; daily protein intake 0.31 g/kg) in random order. The control energy and protein intakes were 12.0 MJ and 1.52 g/kg, respectively. Each test diet period lasted 12 days. On Day 10, antipyrine 1000 mg and metronidazole 500 mg were given and elimination in saliva was determined.