Impact of OATP1B1, MDR1, and CYP3A4 expression in liver and intestine on interpatient pharmacokinetic variability of atorvastatin in obese subjects.

Individual variability in expression and function of organic anion-transporting polypeptide 1B1 (OATP1B1), multidrug resistance protein 1 (MDR1), and/or cytochrome P450 3A4 (CYP3A4) may impact the clinical response of many drugs. We investigated the correlation between expression of these proteins and pharmacokinetics of atorvastatin, a substrate of all three, in 21 obese patients with paired biopsies from liver and intestinal segments. The patients were also screened for the SLCO1B1 c.521T→C variant alleles. Approximately 30% (r(2) = 0.28) of the variation in oral clearance (CL/F) of atorvastatin was explained by hepatic OATP1B1 protein expression (P = 0.041). Patients carrying the SLCO1B1 c.521C variant allele (homozygous, n = 4; heterozygous, n = 2) exhibited 45% lower CL/F of atorvastatin than the c.521TT carriers (P = 0.067). No association between hepatic and intestinal expression of MDR1 or CYP3A4 and atorvastatin pharmacokinetics was found (P > 0.149). In conclusion, this study suggests that OATP1B1 phenotype is more important than CYP3A4 and MDR1 phenotypes for the individual pharmacokinetic variability of atorvastatin.

Beta cell function after weight loss: a clinical trial comparing gastric bypass surgery and intensive lifestyle intervention.

OBJECTIVE: The effects of various weight loss strategies on pancreatic beta cell function remain unclear. We aimed to compare the effect of intensive lifestyle intervention (ILI) and Roux-en-Y gastric bypass surgery (RYGB) on beta cell function. DESIGN: One year controlled clinical trial (ClinicalTrials.gov identifier NCT00273104). METHODS: One hundred and nineteen morbidly obese participants without known diabetes from the MOBIL study (mean (s.d.) age 43.6 (10.8) years, body mass index (BMI) 45.5 (5.6) kg/m², 84 women) were allocated to RYGB (n = 64) or ILI (n = 55). The patients underwent repeated oral glucose tolerance tests (OGTTs) and were categorised as having either normal (NGT) or abnormal glucose tolerance (AGT). Twenty-nine normal-weight subjects with NGT (age 42.6 (8.7) years, BMI 22.6 (1.5) kg/m², 19 women) served as controls. OGTT-based indices of beta cell function were calculated. RESULTS: One year weight reduction was 30% (8) after RYGB and 9% (10) after ILI (P < 0.001). Disposition index (DI) increased in all treatment groups (all P<0.05), although more in the surgery groups (both P < 0.001). Stimulated proinsulin-to-insulin (PI/I) ratio decreased in both surgery groups (both P < 0.001), but to a greater extent in the surgery group with AGT at baseline (P < 0.001). Post surgery, patients with NGT at baseline had higher DI and lower stimulated PI/I ratio than controls (both P < 0.027). CONCLUSIONS: Gastric bypass surgery improved beta cell function to a significantly greater extent than ILI. Supra-physiological insulin secretion and proinsulin processing may indicate excessive beta cell function after gastric bypass surgery.

Obesity-related cardiovascular risk factors after weight loss: a clinical trial comparing gastric bypass surgery and intensive lifestyle intervention.

OBJECTIVE: Weight reduction improves several obesity-related health conditions. We aimed to compare the effect of bariatric surgery and comprehensive lifestyle intervention on type 2 diabetes and obesity-related cardiovascular risk factors. DESIGN: One-year controlled clinical trial (ClinicalTrials.gov identifier NCT00273104). METHODS: Morbidly obese subjects (19-66 years, mean (s.d.) body mass index 45.1 kg/m(2) (5.6), 103 women) were treated with either Roux-en-Y gastric bypass surgery (n=80) or intensive lifestyle intervention at a rehabilitation centre (n=66). The dropout rate within both groups was 5%. RESULTS: Among the 76 completers in the surgery group and the 63 completers in the lifestyle group, mean (s.d.) 1-year weight loss was 30% (8) and 8% (9) respectively. Beneficial effects on glucose metabolism, blood pressure, lipids and low-grade inflammation were observed in both groups. Remission rates of type 2 diabetes and hypertension were significantly higher in the surgery group than the lifestyle intervention group; 70 vs 33%, P=0.027, and 49 vs 23%, P=0.016. The improvements in glycaemic control and blood pressure were mediated by weight reduction. The surgery group experienced a significantly greater reduction in the prevalence of metabolic syndrome, albuminuria and electrocardiographic left ventricular hypertrophy than the lifestyle group. Gastrointestinal symptoms and symptomatic postprandial hypoglycaemia developed more frequently after gastric bypass surgery than after lifestyle intervention. There were no deaths. CONCLUSIONS: Type 2 diabetes and obesity-related cardiovascular risk factors were improved after both treatment strategies. However, the improvements were greatest in those patients treated with gastric bypass surgery.

Significant increase in systemic exposure of atorvastatin after biliopancreatic diversion with duodenal switch.

Biliopancreatic diversion with duodenal switch is a combined restrictive and malabsorptive surgical weight loss procedure. Given that this procedure introduces a bypass of the proximal small intestine, it is a suitable model for investigating the influence of the proximal intestine on drug bioavailability. Eight-hour pharmacokinetic profiles were obtained the day before surgery and again after surgery at (median) 6 weeks (range, 4-8 weeks) in 10 morbidly obese patients who were receiving treatment with 20-80 mg atorvastatin each morning. The bioavailability of atorvastatin acid was significantly increased, with a mean twofold higher AUC(0-8) after surgery (range 1.0-4.2, P = 0.001). Time to maximum plasma concentration (C(max)) increased from 1.2 h before surgery to 2.3 h after surgery (P = 0.03). The results emphasize the protective nature of the proximal small intestine against ingested exogenous compounds. Consequently, retitration to the lowest effective dose should be considered after biliopancreatic diversion with duodenal switch in the case of drugs with a high degree of intestinal first pass metabolism and a narrow therapeutic window.

Significantly altered systemic exposure to atorvastatin acid following gastric bypass surgery in morbidly obese patients.

The impact of gastric bypass on atorvastatin pharmacokinetics was investigated in 12 morbidly obese patients being treated with 20-80 mg atorvastatin each morning. Eight-hour pharmacokinetic investigations were performed the day before the surgery and at a median of 5 weeks (range 3-6 weeks) after the surgery. Gastric bypass surgery produced a variable effect on individual systemic exposure to atorvastatin acid (area under the plasma concentration vs. time curve from 0 to 8 h postdose (AUC(0-8))), ranging from a threefold decrease to a twofold increase (median ratio = 1.1, P = 0.99). Patients with the highest systemic exposure to atorvastatin before surgery showed reduced exposure after surgery (n = 3, median ratio = 0.4, range = 0.3-0.5, P < 0.01), whereas those with lower systemic exposure before surgery showed a median 1.2-fold increase in atorvastatin AUC(0-8) (n = 9, range = 0.8-2.3, P = 0.03) after surgery. This study indicates that the presurgical first-pass metabolic capacity influences the effect of gastric bypass on atorvastatin bioavailability. Because individual first-pass metabolic capacity is not readily assessable clinically, retitration up to the lowest effective dose should be performed after the surgery.

Long-term results of antireflux surgery indicate the need for a randomized clinical trial.

BACKGROUND: Well conducted, comparative trials of laparoscopic versus open antireflux surgery with an adequate patient enrollment are few and they do not demonstrate obvious advantages for the laparoscopic approach except for a marginal gain in shorter hospital stay. The aim of this study was to compare the effectiveness of laparoscopic and open procedures. METHODS: Two unselected groups of 230 patients were identified through a register of all inpatient public care in Sweden. Outcomes of laparoscopic and open antireflux surgery were compared using a disease-specific questionnaire 4 years after operation. RESULTS: Failure and dissatisfaction were significantly more common in the laparoscopy group than among patients having conventional open surgery. Treatment failure rates were 29.0 and 14.6 per cent respectively (P = 0.004). Dissatisfaction rates were 15.0 and 7.0 per cent respectively (P = 0.005). There was no other questionnaire item for which the proportion of failures differed significantly between the two groups. CONCLUSION: This study does not support the presumption that laparoscopic antireflux surgery is to be preferred to the open procedure. It is strongly recommended that a randomized controlled trial be conducted.

Laparoscopic antireflux surgery in routine hospital care.

BACKGROUND: The frequency of antireflux surgery has tripled since laparoscopic techniques were introduced. In Sweden, laparoscopic antireflux surgery is often done at local hospitals with a very low annual number of patients. Many surgeons. who may have limited experience with conventional antireflux surgery, have started to perform laparoscopic antireflux procedures, in spite of the well-known fact that there is a long learning curve for laparoscopic antireflux surgery. METHODS: A random sample of 225 of 660 patients operated on at high-volume and all 220 patients from low-volume hospitals were identified through a nation-wide register. Outcome 4 years after laparoscopic antireflux surgery was studied using a disease-specific questionnaire. RESULTS: Treatment failures were more common in the high-volume group than among patients operated on at low-volume hospitals, 29.0% and 19.7%, respectively. In the high volume group, medication (specifically to relieve heartburn or acid regurgitation) was taken at least once a week and revisional surgery was found in 19.5% and 6.0%, respectively. Corresponding results in the low-volume group were 11.1% and 2.9%, respectively. None of these differences was statistically significant at the overall 0.05 level. CONCLUSION: A failure rate of almost 30% at 4 years' follow-up for patients operated on at relatively high-volume hospitals was disappointing, despite the fact that these results are population-based. Hospitals are encouraged to provide accounts of their results in an effort to identify the reasons for treatment failures, and for the public to have access to more objective information on different therapeutic options.

Optimal positive end-expiratory pressure (PEEP) settings in differential lung ventilation during simultaneous unilateral pneumothorax and laparoscopy: an experimental study in pigs.

BACKGROUND: A combined thoraco-laparoscopic technique for esophageal resection is technically possible, but it requires special attention to ventilation. The positive insufflation pressure normally used in laparoscopy will, when communication between thorax and abdomen is established, create a pneumothorax. METHODS: We performed an experimental study of differential lung ventilation with different levels of positive end-expiratory pressure (PEEP) settings during thoraco-laparoscopy in anesthetized pigs. RESULTS: Positive pressure insufflation of carbon dioxide (CO2) resulted in elevated pulmonary capillary wedge pressure, hypercarbia, and respiratory acidosis. Hypoxemia, however, developed only at lower settings of PEEP. Heart rate, mean arterial pressure, and cardiac output remained relatively stable. CONCLUSION: Pneumopleuroperitoneum under positive CO2 insufflation pressure had adverse effects on blood gases. Hypercarbia, respiratory acidosis, and hypoxemia were early manifestations that occurred even in the presence of hemodynamic stability. The application of PEEP equal to or above CO2 insufflation pressure improved blood gases; in particular, the hypoxia could be avoided. No beneficial effects of differential lung ventilation were documented.

The economics of laparoscopic antireflux operations compared with open surgery.

In Sweden laparoscopic antireflux surgery started in 1991, and within four years replaced the open procedure as the method of choice. It is, however, not yet settled which of the two techniques is most cost effective. To compare these two operations in economic terms we studied all reports up to September 1997 as well as the register in the epidemiological unit of the National Board of Health and Welfare (EpC). We found numerous reports on consecutive series of laparoscopic procedures, several non-randomised studies, and only one randomised prospective study comparing open and laparoscopic antireflux surgery. The few studies about the economics of antireflux surgery indicated that hospital costs were equal or less for the laparoscopic procedure. If one adds the costs from loss of production (sick leave) it will be an even more favourable outcome for the laparoscopic treatment. The figures from EpC showed that antireflux surgery is done infrequently in many surgical departments. This may have a substantial influence on the economic outcome as well as the effectiveness of antireflux surgery in Sweden. Few studies have compared open and laparoscopic methods from an economic perspective. As a tool for cost benefit analysis these reports are incomplete.

Antireflux surgery in Sweden, 1987-1997: a decade of change.

BACKGROUND: The aim of this study was to analyse whether new therapeutic options--the introduction of proton-pump inhibitors (PPI) in 1989 and the laparoscopic technique in 1992--altered the surgical treatment of gastro-oesophageal reflux disease (GORD) in Sweden. METHODS: Data obtained from the Centre for Epidemiology (EpC) on patients undergoing surgery for GORD from 1987 to 1997 was analysed, and the information was validated with a questionnaire to all surgical departments. RESULTS: The questionnaire gave a response rate of 94%, and the figures corresponded well with those obtained from the EpC. In 1987, 456 antireflux procedures were performed. Ten years later this figure had increased to 1303. This approximately threefold increase started before the introduction of PPI and was even more pronounced during the following few years. The development of laparoscopic antireflux surgery did not alter this increase. In 1997, 76% of the procedures were performed laparoscopically. The fundoplication rate rose from 5.5 to 12.7 procedures/100,000 inhabitants. The rates varied greatly among different counties; 7 of 23 still had a fundoplication rate of less than 10 in 1997. The median number of procedures per hospital in 1997 was 10. Only two departments accomplished more than 50 antireflux procedures. CONCLUSION: Within 5 years the laparoscopic technique replaced the open procedure as the method of choice. However, the increase in the frequency of antireflux surgery was apparent even before the introduction of laparoscopy.