Summary

Aim : The gastrointestinal transit of sequentially administered capsules was investigated in relation to the availability of fluid along the intestinal lumen by magnetic resonance imaging.



Methods : Water-sensitive magnetic resonance imaging was performed on 12 healthy subjects during fasting and 1 h after a meal. Specifiable non-disintegrating capsules were administered at 7, 4 and 1 h prior to imaging.



Results : While food intake reduced the mean fluid volumes in the small intestine (105 ± 72 mL vs. 54 ± 41 mL, P < 0.01) it had no significant effect on the mean fluid volumes in the colon (13 ± 12 mL vs. 18 ± 26 mL). The mean number of separated fluid pockets increased in both organs after meal (small intestine: 4 vs. 6, P < 0.05; large intestine: 4 vs. 6, P < 0.05). The distribution of capsules between the small and large intestine was strongly influenced by food (colon: 3 vs. 17 capsules, P < 0.01).



Conclusions : The results show that fluid is not homogeneously distributed along the gut, which likely contributes to the individual variability of drug absorption. Furthermore, transport of fluid and solids through the ileocaecal valve is obviously initiated by a meal-induced gastro-ileocaecal reflex.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2036.2005.02683.x

Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging

Ezetimibe is the first lipid-lowering drug that inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. Following oral administration, ezetimibe is rapidly absorbed and extensively metabolised (>80%) to the pharmacologically active ezetimibe-glucuronide. Total ezetimibe (sum of 'parent' ezetimibe plus ezetimibe-glucuronide) concentrations reach a maximum 1-2 hours post-administration, followed by enterohepatic recycling and slow elimination. The estimated terminal half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours. Consistent with the elimination half-life of ezetimibe, an approximate 2-fold accumulation is observed upon repeated once-daily administration. The recommended dose of ezetimibe 10 mg/day can be administered in the morning or evening without regard to food. There are no clinically significant effects of age, sex or race on ezetimibe pharmacokinetics and no dosage adjustment is necessary in patients with mild hepatic impairment or mild-to-severe renal insufficiency. The major metabolic pathway for ezetimibe consists of glucuronidation of the 4-hydroxyphenyl group by uridine 5'-diphosphate-glucuronosyltransferase isoenzymes to form ezetimibe-glucuronide in the intestine and liver. Approximately 78% of the dose is excreted in the faeces predominantly as ezetimibe, with the balance found in the urine mainly as ezetimibe-glucuronide. Overall, ezetimibe has a favourable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between ezetimibe and a variety of drugs commonly used in patients with hypercholesterolaemia. Ezetimibe does not have significant effects on plasma levels of HMG-CoA reductase inhibitors commonly known as statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), fibric acid derivatives (gemfibrozil, fenofibrate), digoxin, glipizide, warfarin and triphasic oral contraceptives (ethinylestradiol and levonorgestrel). Concomitant administration of food, antacids, cimetidine or statins had no significant effect on ezetimibe bioavailability. Although coadministration with gemfibrozil and fenofibrate increased the bioavailability of ezetimibe, the clinical significance is thought to be minor considering the relatively flat dose-response curve of ezetimibe and the lack of dose-related increase in adverse events. In contrast, coadministration with the bile acid binding agent colestyramine significantly decreased ezetimibe oral bioavailability (based on area under the plasma concentration-time curve of total ezetimibe). Hence, ezetimibe and colestyramine should be administered several hours apart to avoid attenuating the efficacy of ezetimibe. Finally, higher ezetimibe exposures were observed in patients receiving concomitant ciclosporin, and ezetimibe caused a small but statistically significant effect on plasma levels of ciclosporin. Because treatment experience in patients receiving ciclosporin is limited, physicians are advised to exercise caution when initiating ezetimibe in the setting of ciclosporin coadministration, and to carefully monitor ciclosporin levels.

Ezetimibe : A review of its metabolism, pharmacokinetics and drug interactions

In order to assess the significance of drug/substance levels measured in intensive care medicine and clinical and forensic toxicology as well as for therapeutic drug monitoring, it is essential that a comprehensive collection of data is readily available. We revisited and expanded our 2012 compilation of therapeutic and toxic plasma concentration ranges as well as half-lives of now more than 1100 drugs and other xenobiotics. Data have been abstracted from original papers, text books, and previous compilations and have been completed with data collected in our own forensic and clinical toxicology laboratories. We compiled the data presented in the table and the corresponding annotations over the past 30+ years. A previous compilation was completely double-checked, revised, and updated, if necessary. In addition, more than 200 substances, especially drugs who have been introduced since 2012 to the market as well as illegal drugs and other xenobiotics which became known to cause intoxications were added. We carefully referenced all data. Moreover, the annotations providing details were updated and revised, when necessary. For more than 1100 drugs and other xenobiotics, therapeutic (“normal”) and, if data was available, toxic, and comatose-fatal plasma/blood concentrations as well as elimination half-lives were compiled in a table. In case of intoxications, the blood concentration of the substance and/or metabolite better predicts the clinical severity of the case when compared to the assumed amount and time of ingestion. Comparing and contrasting the clinical case against the data provided, including the half-life, may support the decision for or against further intensive care. In addition, the data provided are useful for the therapeutic monitoring of pharmacotherapies, to facilitate the diagnostic assessment and monitoring of acute and chronic intoxications as well as to support forensic and clinical expert opinions.

/pdf/revisited-therapeutic-and-toxic-blood-concentrations-of-more-2xcqprqwd7.pdf

Revisited: Therapeutic and toxic blood concentrations of more than 1100 drugs and other xenobiotics.

Study of surfactant combinations and development of a novel nanoemulsion for minimising variations in bioavailability of ezetimibe.

Background
Dietary fat is the most important energy source of all the nutrients. Fatty acids, stored as triacylglycerols in the body, are an important reservoir of stored energy and derive primarily from animal fats and vegetable oils.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/eci.12161

New insights into the molecular mechanism of intestinal fatty acid absorption.

A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe

Gout flares may increase risk of cardiovascular events.[1]Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are associated with lower risk of incident gout (primary prevention); however, their role in recurrent flares among gout patients (secondary prevention), and their cardiovascular risk remains unknown.To assess rate of recurrent gout flares in prevalent gout patients with type 2 diabetes initiating SGLT2i versus dipeptidyl peptidase-4 inhibitors (DPP4i), two second-line glucose-lowering agents for type 2 diabetes.This new-user, active comparator cohort study used administrative health data covering nearly all residents of British Columbia, Canada from Jan 2014 to June 2022, including all dispensed prescriptions, regardless of funder. Primary outcome was recurrent gout flare counts, ascertained by emergency department (ED), hospitalization, outpatient, and medication dispensing records.[1]We also restricted to flares requiring hospitalization or ED visit, and stratified by sex, age, gout intensity (presence of ≥1 gout-coded encounter or colchicine dispensing over past year) and diuretic and urate-lowering therapy (ULT) use. Myocardial infarction and stroke were secondary outcomes. We also assessed genital infection as positive control and osteoarthritis as negative control. Poisson and Cox proportional hazards models were used with 1:1 propensity matching.We included 8150 gout patients with type 2 diabetes (mean age 66, 71% male, 59% with cardiovascular disease). Flare rate was lower among SGLT2i initiators (52.4 events per 1000 person-years) than DPP4i initiators (79.7 events per 1000 person-years): rate ratio (RR) 0.66 (95% CI: 0.57, 0.75) and rate difference (RD) -27.4 (-36.0, -18.7). RR and RD for flares requiring hospitalization or ED visit were 0.52 (0.32, 0.84) and -3.4 (-5.8, -0.9), respectively.Results were consistent regardless of sex or age (Table 1). RR was also consistent regardless of baseline gout intensity or diuretic or ULT use, though absolute RD was higher in patients with greater gout intensity: -71.6 [-111.1, -32.1] vs. 20.8 [-28.8, -12.7] per 1000 person-years, respectively.Hazard ratio (HR) and RD were 0.69 (0.54, 0.88) and -7.6 (-12.4, -2.8) per 1000 person-years for myocardial infarction; HR, 0.81 (0.62, 1.05) for stroke. For control outcomes, SGLT2i initiators had higher risk of genital infection, while there was no difference in risk of osteoarthritis (Table 1).For gout patients, SGLT2i may offer pleiotropic cardiovascular and recurrent flare frequency benefits.[1] Cipolletta et al.JAMA2022Table 1.Recurrent gout flare count and cardiovascular and control outcomes among gout patients with type 2 diabetes, after propensity-score matchingSGLT2i compared with DPP4i [Reference]Gout Flare CountRate Ratio (95% CI)Rate Difference (95% CI)Overall (Primary outcome)0.66 (0.57, 0.75)-27.4 (-36.0, -18.7)Flares requiring hospitalization or emergency visits0.52 (0.32, 0.84)-3.4 (-5.8, -0.9)SubgroupsSexMen0.63 (0.54, 0.73)-33.6 (-44.3, -22.8)Women0.43 (0.29, 0.62)-35.0 (-48.9, -21.0)Age≤ 65 years0.69 (0.56, 0.85)-22.9 (-35.8. -10.0)> 65 years0.51 (0.42, 0.62)-45.3 (-58.0, -32.6)Baseline diuretic useYes0.75 (0.62, 0.92)-24.8 (-42.1, -7.5)No0.63 (0.52, 0.77)-24.1 (-34.2, -14.1)Baseline urate-lowering therapy useYes0.66 (0.50, 0.87)-25.2 (-41.8, -8.6)No0.56 (0.48, 0.66)-39.5 (-50.4, -28.7)Baseline gout intensityHigher0.65 (0.51, 0.82)-71.6 (-111.1, -32.1)Lower0.64 (0.53, 0.76)-20.8 (-28.8, -12.7)Cardiovascular OutcomesHazard Ratio (95% CI)Risk Difference (95% CI)Myocardial infarction0.69 (0.54, 0.88)-7.6 (-12.4, -2.8)Stroke0.81 (0.62, 1.05)-3.9 (-8.3, 0.4)Control OutcomesHazard Ratio (95% CI)Risk Difference (95% CI)Genital infection (POSITIVE)2.15 (1.39, 3.30)5.0 (2.2, 7.9)Osteoarthritis (NEGATIVE)1.07 (0.95, 1.20)4.4 (-6.8, 15.7)SGLT2i, sodium glucose cotransporter-2 inhibitors; DPP4i, dipeptidyl peptidase 4 inhibitorsNIL.Natalie McCormick: None declared, Chio Yokose: None declared, Jie Wei: None declared, Leo Lu: None declared, Deborah Wexler Consultant of: Served on Data Monitoring Committees for Novo Nordisk, J. Antonio Aviña-Zubieta: None declared, Mary De Vera: None declared, Yuqing Zhang: None declared, Hyon Choi Consultant of: Ironwood, Selecta, Horizon, Takeda, Kowa, and Vaxart., Grant/research support from: Ironwood and Horizon.

/pdf/op0156-initiation-of-sodium-glucose-cotransporter-2-1tec4bgd.pdf

Op0156 initiation of sodium-glucose cotransporter-2 inhibitors and recurrent gout flares in gout patients with type 2 diabetes: a general population-based cohort study

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A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe

Op0156 initiation of sodium-glucose cotransporter-2 inhibitors and recurrent gout flares in gout patients with type 2 diabetes: a general population-based cohort study