Morphine and metabolites plasma levels after administration of sustained release morphine in Roux-en-Y gastric bypass subjects versus matched control subjects

International audienceBackground: Better knowledge of opioid pharmacology after Roux-en-Y gastric bypass (RYGB) is required for optimizing their use in this growing population.Objective: The aim of this case-controlled pharmacokinetic (PK) study was to compare morphine and its glucuronidated metabolites (morphine-3-glucuronide and morphine-6-glucuronide) plasma PKs between patients with RYGB and their controls.Settings: University hospital, Lariboisière Hospital, Paris.Methods: Thirty milligrams of morphine as a sustained-release formulation was orally administered in 12 women who had undergone RYGB for at least 2 years (RYGB group) and in their nonsurgical controls matched for sex, body mass index (±2 points), and age (±5 yr). Morphine, morphine-3-glucuronide, and morphine-6-glucuronide plasma concentrations over a 12-hour period were determined by a validated method using liquid chromatography mass spectrometry in tandem. Drowsiness, respiratory rate, and oxygen saturation were monitored during the PK visit.Results: Morphine oral area under the curve (for time 0-12 hr; 115.8 ± 108.0 nmol.hr/L and 86.9 ± 38.8 nmol.hr/L for RYGB group and control group, respectively, P = .71), morphine at maximal concentration, metabolites oral area under the curve (for time 0-12 hr), and other PK parameters were similar between groups. After drug administration, mean drowsiness was superior in RYGB group. Mean respiratory rate and oxygen saturation were similar in both groups.Conclusion: No dose adjustment seems to be needed for sustained release morphine when prescribed to RYGB patients

Markers of Individual Drug Metabolism: Towards the Development of a Personalized Antidepressant Prescription

The development of a personalized psychopharmacotherapy could potentially reduce treatment failure associated with drug intolerance or resistance, and therefore the burden and costs of affective disorders. An important challenge in realising this potential will be to identify suitable markers of an individual's metabolic response to specific pharmaceuticals. In the absence of suitable markers related directly to drug mechanism, the drug-metabolizing enzymes and transporters have emerged as major determinants of variability in drug metabolism and response. In keeping with this emergent general pharmacological trend, numerous studies concerning the relationship between antidepressants, their metabolism, transport, pharmacokinetic properties, efficacy and tolerability have now been published. These studies are reviewed in this article. The studies considered here frequently support a link between enzyme/transporter activity and/or the pharmacokinetic parameters of antidepressants. However, the majority of studies explored the variability of tricyclic antidepressants, which are less often prescribed today. Furthermore only a few studies have been conducted in naturalistic clinical conditions, seeking to determine whether the systematic assessment of the variability may improve the management of 'real-world' patients. Nonetheless recent studies have yielded promising results regarding the potential benefits of determining drug metabolism variability which might encourage additional large-scale prospective systematic studies be set up to assess the relevance of this approach in everyday practice

The effect of morbid obesity on morphine glucuronidation

International audienceThe purpose of the present work was to study the change in morphine metabolic ratio in obese subjects before and after Roux-en-Y Gastric Bypass (RYGB) and to identify clinical and/or biological factors associated with this change. The pharmacokinetics (PK) of oral morphine (30mg), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was performed in patients before (n=25; mean BMI=43.2 (35.4-61.9)kg/m2), 7-15days (n=16) and 6 months after RYGB (n=19; mean BMI=32.3 (25.4-46.0)kg/m2). Morphine Cmax and AUC0-inf were significantly increased and morphine Tmax significantly shortened at 6 months after RYGB compared with preoperative data, indicating an important increase in the rate and extent of morphine absorption. The morphine metabolic ratio 0-inf M3G+M6G/Morphine, decreased significantly from the preoperative to 6 months postoperative period with an average of -26% (range -74%; +21%; p=0.004), but not in the immediate post-operative period. The change in morphine metabolic ratio was associated with a change in BMI, fat mass in kg, and triglyceride levels (rho=0.5, p≤0.04). The degree of change in several markers of low-grade inflammation, or the level of liver steatosis and fibrosis before surgery, was not associated with the change in morphine metabolic ratios. Our findings indicate that RYGB-induced weight loss significantly decreases morphine metabolic ratio, arguing for an effect of morbid obesity on glucuronidation. With glucuronide exposure at 6 months similar to preoperative values, a higher morphine AUC0-inf should encourage reducing morphine dosage in patients undergoing RYGB and chronically receiving immediate-release oral morphine

[Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): results obtained in France]

AIM: Information about the variation in the risk for venous thromboembolism (VTE) and in prophylaxis practices in France and around the world is scarce. METHODS: The Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting (ENDORSE) study is a multinational cross-sectional survey designed to assess the prevalence of VTE risk in the acute hospital care setting, and to determine the proportion of at-risk patients who receive effective prophylaxis, in accordance with the 2004 American College of Chest Physicians (ACCP) guidelines. This paper gives the results of the ENDORSE study in the French centres in comparison with the global worldwide results of the ENDORSE study and with other Western Europe countries. RESULTS: In France, 18 randomized hospitals participated to the study between august 2006 and January 2007. 2844 patients were evaluated (917 from chirurgical wards and 1927 from medical wards). One thousand four hundred and nineteen patients (49.9%) were at VTE risk (78.3% in chirurgical wards and 36.4% in medical wards). Of the 1419 patients at VTE risk, 62.4% received ACCP-recommended VTE prophylaxis (71.2% in chirurgical wards and 53.5% in medical wards). VTE Prophylaxis in France (62.4%) is more frequent than worldwide in the international ENDORSE study (50.2%) and similar to the majority of the other western European countries and the USA. It is also more used in university hospitals (66.9%) than in other hospitals (58.9%). Prophylaxis in patients at risk for VTE was presented in 43% patients with acute heart failure, 53% with non-infectious acute respiratory failure, 57% in patients with pulmonary infection, 56% in patients with stroke, 55% in patients with active cancer and 48% in patients with non-pulmonary sepsis. CONCLUSIONS: The ENDORSE study has shown a high level of patients at risk for VTE in the population of hospitalized patients in France. The rate of prophylaxis for VTE remained low, in particular in Medicine wards. Our data reinforced the rationale for the use of hospital-wide strategies to assess patients\u27 VTE risk and to implement measures that ensure that at-risk patients receive appropriate prophylaxis, in particularly in medical patients