Impact of obesity and roux-en-Y gastric bypass on the pharmacokinetics of (R)- and (S)-omeprazole and intragastric pH.

This study employed physiologically-based pharmacokinetic-pharmacodynamics (PBPK/PD) modeling to predict the effect of obesity and gastric bypass surgery on the pharmacokinetics and intragastric pH following omeprazole treatment. The simulated plasma concentrations closely matched the observed data from non-obese, morbidly obese, and post-gastric bypass populations. Obesity significantly reduces CYP3A4 and CYP2C19 activities, as reflected by the metabolic ratio [omeprazole sulphone]/[omeprazole] and [5-hydroxy-omeprazole]/[omeprazole]. The morbidly obese model accounted for the down-regulation of CYP2C19 and CYP3A4 to recapitulate the observed data. Sensitivity analysis showed that intestinal CYP3A4, gastric pH, small intestine bypass, and the delay in bile release do not have a major influence on omeprazole exposure. Hepatic CYP3A4 had a significant impact on the AUC of (S)-omeprazole, while hepatic CYP2C19 affected both (R)- and (S)-omeprazole AUC. After gastric bypass surgery, the activity of CYP3A4 and CYP2C19 is restored. The PBPK model was linked to a mechanism-based PD model to assess the effect of omeprazole on intragastric pH. Following 40 mg omeprazole, the mean intragastric pH was 4.3, 4.6, and 6.6 in non-obese, obese, and post-gastric bypass populations, and the daily time with pH >4 was 14.7, 16.4, and 24 h. Our PBPK/PD approach provides a comprehensive understating of the impact of obesity and weight loss on CYP3A4 and CYP2C19 activity and omeprazole pharmacokinetics. Given that simulated intragastric pH is relatively high in post-RYGB patients, irrespective of the dose of omeprazole, additional clinical outcomes are imperative to assess the effect of proton pump inhibitor in preventing marginal ulcers in this population.

Delayed Lithium Reintoxication in a Case of Severe Multidrug Intoxication: A Case Study.

ABSTRACT: The authors present a case of severe multidrug intoxication following massive ingestion of lithium, nortriptyline, aripiprazole, lorazepam, and temazepam. After initial treatment, serum lithium levels decreased significantly. However, 28 hours post ingestion, recurrent elevated lithium levels were observed, and serum lithium level increased 0.71 mmol/L in 12 hours. The intensivist consulted a hospital pharmacist about this. After administering clearance-inducing therapy using continuous venovenous hemodialysis, the lithium level was reduced to a long-lasting nontoxic level. The occurrence of secondary elevation in lithium levels exceeding the toxic limit in cases of massive ingestion of lithium tablets, whether in combination with anticholinergic drugs, should be anticipated. Close monitoring and prompt initiation of clearance-inducing therapy can improve clinical outcomes.

The Effect of Roux-en-Y Gastric Bypass Surgery in Morbidly Obese Patients on Pharmacokinetics of (Acetyl)Salicylic Acid and Omeprazole: the ERY-PAO Study.

BACKGROUND: Data on the absorption of orally administered drugs following Roux-en-Y gastric bypass (RYGB) surgery in obese patients are limited and inconclusive. As it is difficult to predict changes in absorption, studies on frequently used drugs in this population are necessary. Acetylsalicylic acid (ASA) and omeprazole are two commonly prescribed drugs in obese patients. METHODS: In this repeated measures study, omeprazole and salicylic acid (SA) serum concentrations were measured before and after RYGB in 34 morbidly obese subjects. Time to maximum concentration (Tmax), lag time (Tlag), maximum concentration (Cmax), and area under the serum concentration versus time curve (AUC) were calculated for both drugs to determine possible differences in drug absorption after the procedure. RESULTS: For SA, Tmax significantly decreased after RYGB, while both Cmax and AUC0-24 significantly increased. For omeprazole, both Tmax and Tlag significantly decreased after RYGB, while Cmax significantly increased. Mean AUC0-12 significantly decreased post-surgery. The difference in AUC0-12 before and after surgery varied between subjects. CONCLUSIONS: Our study shows a faster absorption of both ASA and omeprazole after RYGB. The exposure to ASA is higher post-surgery, but the standard dose of 80 mg does not need to be modified, considering its range in effective dose. The exposure to omeprazole is, on average, decreased after surgery. Clinicians should be aware to increase the dose of omeprazole if symptoms suggest inadequate response.

[Metformin, renal function and lactate: the MetClear Study]. / Metformine, nierfunctie en lactaat: het MetClear-onderzoek.

OBJECTIVE: To map the relation between metformin prescription and renal function in an outpatient setting. To investigate whether there is an association between renal function, metformin concentration and lactate concentration. DESIGN: Pilot for a prospective observational cohort study. METHOD: We included outpatients with diabetes mellitus type 2 who were treated with metformin. At inclusion, we determined the HbA1c, lactate, metformin and creatinine concentrations and the estimated glomerular filtration rate (eGFR). Information on the prescribed dosage of metformin was acquired from patient files. Our primary outcome measure was the number of patients in whom the dose was not adjusted to the renal function. Our secondary outcome measure was the difference in median lactate concentration between patients with a normal (≤ 2.5 mg/l) and an increased (> 2.5 mg/l) metformin concentration. RESULTS: Eighty-eight patients were included, 12 (14%) of whom had an eGFR ≤ 30, 31 (36%) an eGFR of 30-50 and 44 (50%) an eGFR > 51 ml/min/1.73 m2. In 27 (31%) of all patients, the daily dose of metformin exceeded the dose recommended in the practice guidelines. The 28 patients with an increased metformin concentration had a significantly higher median lactate concentration: 2.3 mmol/l compared to 1.5 mmol/l for the 60 patients with a normal metformin concentration (p < 0.0001). CONCLUSION: Our study shows that in outpatient practice, the metformin dose is not sufficiently adjusted to a reduced renal function in 31% of the patients. The accumulation of metformin appears to be associated with an increased lactate concentration and a reduced renal function. Extra attention to the dose of metformin in reduced renal clearance is therefore recommended.