title: Drug disposition before and after gastric bypass: fenofibrate and posaconazole. Pharmacokinetics and pharmacodynamics of single doses of rivaroxaban in obese patients prior to and after bariatric surgery Long-term effects of gastric bypass and duodenal switch on systemic exposure of atorvastatin 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 Significant Increase in Systemic Exposure of Atorvastatin After Biliopancreatic Diversion With Duodenal Switch The role of CYP2C and CYP3A in the disposition of 3-keto-desogestrel after administration of desogestrel. The Delay of Gastric Emptying Induced by Remifentanil Is Not Influenced by Posture Orally Administered Ranitidine Plasma Concentrations before and after Biliopancreatic Diversion in Morbidly Obese Patients Comparison of Bioavailability of Single‐Dose Extended‐Release Venlafaxine Capsules in Obese Patients Before and After Gastric Bypass Surgery Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A. Proximal Roux-en-Y gastric bypass alters drug absorption pattern but not systemic exposure of CYP3A4 and P-glycoprotein substrates. The effect of gastric bypass on the pharmacokinetics of serotonin reuptake inhibitors. Sleeve Gastrectomy in Morbidly Obese HIV Patients: Focus on Anti-retroviral Treatment Absorption After Surgery Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. Caffeine as a probe for CYP1A2 activity: potential influence of renal factors on urinary phenotypic trait measurements. Effect of a Roux-en-Y Gastric Bypass on the Pharmacokinetics of Oral Morphine Using a Population Approach Biological effects of a new and potent progestagen. A clinical study. Plasma concentrations of etonogestrel in women using oral desogestrel before and after Roux‐en‐Y gastric bypass surgery: a pharmacokinetic study The effect of bariatric surgery on the direct oral anticoagulant rivaroxaban: the extension study. Impact of Bariatric Surgery on the Pharmacokinetics Parameters of Amoxicillin Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Drug disposition and modelling before and after gastric bypass: immediate and controlled-release metoprolol formulations.
abstract: AIMS Roux-en-Y gastric bypass ( RYGB ) alters the anatomical structure of the gastrointestinal tract , which can result in alterations in drug disposition . The aim of the present study was to evaluate the oral disposition of two compounds belonging to the Biopharmaceutical Classification System Class II - fenofibrate ( bile salt-dependent solubility ) and posaconazole ( gastric pH-dependent dissolution ) - before and after RYGB in the same individuals . METHODS A single-dose pharmacokinetic study with two model compounds - namely , 67 mg fenofibrate ( Lipanthyl ® ) and 400 mg posaconazole ( Noxafil ® ) - was performed in 12 volunteers pre- and post-RYGB . After oral administration , blood sample s were collected at different time points up to 48 h after administration . Plasma concentrations were determined by high-performance liquid chromatography in order to calculate the area under the concentration-time curve up to 48 h ( AUC0 - 48 h ) , the peak plasma concentration ( Cmax ) and the time to reach peak concentration ( Tmax ) . RESULTS After administration of fenofibrate , no relevant differences in AUC0 - 48 h , Cmax and Tmax between the pre- and postoperative setting were observed . The geometric mean of the ratio of AUC0 - 48 h post/pre-RYGB for fenofibrate was 1.10 [ 95 % confidence interval ( CI ) 0.87 , 1.40 ; P = 0.40 ] . For posaconazole , an important decrease in AUC0 - 48 h and Cmax following RYGB was shown ; the geometric mean of the AUC0 - 48 h post/pre-RYGB ratio was 0.68 ( 95 % CI 0.48 , 0.96 ; P = 0.03 ) and the geometric mean of the Cmax pre/post-RYGB ratio was 0.60 ( 95 % CI 0.39 , 0.94 ; P = 0.03 ) . The decreased exposure of posaconazole could be explained by the increased gastric pH and accelerated gastric emptying of fluids post-RYGB . No difference for Tmax was observed . CONCLUSIONS The disposition of fenofibrate was not altered after RYGB , whereas the oral disposition of posaconazole was significantly decreased following RYGB AIMS Venous thromboembolism is an important cause of postoperative morbidity and mortality in bariatric surgery . Studies of direct oral anticoagulants ( DOACs ) are not available in this surgical field . The objective of this phase 1 clinical trial was to investigate pharmacokinetic and pharmacodynamic ( PK/PD ) parameters of rivaroxaban in bariatric patients . METHODS In this single-centre study , obese patients received single oral doses of rivaroxaban ( 10 mg ) 1 day prior to and 3 days after bariatric surgery . PK and PD parameters were assessed at baseline and during 24 h after drug ingestion . RESULTS Six Roux-en-Y gastric bypass patients and six sleeve gastrectomy patients completed the study .  Mean rivaroxaban area under plasma concentration-time curve , peak plasma concentration , time to peak plasma concentration and terminal half-life were 971.9 μg·h l-1 ( coefficient of variation : 10.6 ) , 135.3 μg l-1 ( 26.7 ) , 1.5 h and 13.1 h ( 34.1 ) prior to and 1165.8 ( 21.9 ) , 170.0 ( 15.9 ) , 1.5 and 8.9 ( 44.6 ) postsurgery for SG patients and 933.7 μg·h l-1 ( 22.3 ) , 136.5 μg l-1 ( 10.7 ) , 1.5 h und 13.8 h ( 46.6 ) prior to and 1029.4 ( 7.4 ) , 110.8 ( 31.8 ) , 2.5 and 15 ( 60.0 ) postsurgery for Roux-en-Y gastric bypass patients , respectively . Prothrombin fragments ( F1 + 2 ) decreased during the first 12 hours and increased thereafter in the pre- and the postbariatric setting . Thrombin-antithrombin complexes dropped within 1 - 3 h in the prebariatric setting and remained low after surgery until they increased at 24 h postdose  . Rivaroxaban was well tolerated and no relevant safety issues were observed . CONCLUSIONS Bariatric surgery does not appear to alter PK of rivaroxaban in a clinical ly relevant way . Effective prophylactic postbariatric anticoagulation is supported by changes in PD Background A previous study of 22 patients undergoing either gastric bypass or duodenal switch showed increased systemic exposure of atorvastatin acid  3–8 weeks after surgery in the majority of patients . This study aim ed to investigate the long-term effects on systemic exposure of atorvastatin acid in the same group of patients . Methods An 8-h pharmacokinetic investigation was performed a median of 27 months ( range 21–45 months ) after surgery . Systemic exposure was measured as the area under the plasma concentration versus the time curve from 0 to 8 h postdose ( AUC0–8 ) . Linear mixed models with AUC0–8 as the dependent variable were implemented to assess the effect of time , surgical procedure , and body mass index ( BMI ) as explanatory variables . Results The study enrolled 20 patients . The systemic exposure of atorvastatin acid changed significantly over time ( p = 0.001 ) , albeit there was substantial variation between subjects . The effect of time was attenuated but remained significant after adjustment for surgical procedure and BMI ( p = 0.048 ) . The initial AUC0–8 increase seen in the majority of patients 3–8 weeks after surgery was normalized long term , with 7 of the 12 gastric bypass patients and 6 of the 8 duodenal switch patients showing decreased AUC0–8 compared with preoperative values . Conclusions The systemic exposure of atorvastatin showed a significant change over time after bariatric surgery , albeit with large inter- and intraindividual variations . The findings indicate that patients using  atorvastatin  or drugs with similar pharmacokinetic properties should be monitored closely for both therapeutic effects and adverse events the first years after gastric bypass and duodenal switch . Clinical Trial NCT00331565 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 st and ard 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 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 AUC0–8 after surgery ( range 1.0–4.2 , P = 0.001 ) . Time to maximum plasma concentration ( Cmax ) 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 AIMS Our objective was to study in vivo the role of CYP2C and CYP3A4 in the disposition of 3-keto-desogestrel after administration of desogestrel , by using the selective inhibitors fluconazole ( CYP2C ) and itraconazole ( CYP3A4 ) . METHODS This study had a three-way crossover design and included 12 healthy females , the data from 11 of whom were analyzed . In the first ( control ) phase all subjects received a single 150 microg oral dose of desogestrel alone . In the second and third phases subjects received a 4 day pretreatment with either 200 mg fluconazole or 200 mg itraconazole once daily in a r and omized balanced order . Desogestrel was given 1 h after the last dose of the CYP inhibitor . Plasma 3-keto-desogestrel concentrations were determined for up to 72 h post dose . RESULTS Pretreatment with itraconazole for 4 days significantly increased the area under the plasma concentration-time curve ( AUC ) of 3-keto-desogestrel by 72.4 % ( 95 % confidence interval on the difference 12 % , 133 % ; P = 0.024 ) compared with the control phase , whereas fluconazole pretreatment had no significant effect ( 95 % CI on the difference -42 % , 34 % ) . Neither enzyme inhibitor affected significantly the maximum concentration ( 95 % CI on the difference 14 % , 124 % for itraconazole and -23 % , 40 % for fluconazole ) or elimination half-life ( 95 % CI on the difference -42 % , 120 % for itraconazole and -24 % , 61 % for fluconazole ) of 3-keto-desogestrel . CONCLUSIONS According to the present study , the biotransformation of desogestrel to 3-keto-desogestrel did not appear to be mediated by CYP2C9 and CYP2C19 as suggested earlier . However , the further metabolism of 3-keto-desogestrel seems to be catalyzed by CYP3A4 Posture has an effect on gastric emptying . In this study , we investigated whether posture influences the delay in gastric emptying induced by opioid analgesics . Ten healthy male subjects underwent 4 gastric emptying studies with the acetaminophen method . On two occasions the subjects were given a continuous infusion of remifentanil ( 0.2 μg · kg−1 · min−1 ) while lying either on the right lateral side in a 20 ° head-up position or on the left lateral side in a 20 ° head-down position . On two other occasions no infusion was given , and the subjects were studied lying in the two positions . When remifentanil was given , there were no significant differences between the two postures in maximal acetaminophen concentration ( right side , 34 μmol · L−1 ; versus left side , 16 μmol · L−1 ) , time taken to reach the maximal concentration ( 94 versus 109 min ) , or area under the serum acetaminophen concentration time curve from 0 to 60 min ( 962 versus 197 min · μmol · L−1 ) . In the control situation , there were differences between the postures in maximal acetaminophen concentration ( 138 versus 94 μmol · L−1 ; P < 0.0001 ) and area under the serum acetaminophen concentration time curves from 0 to 60 min ( 5092 versus 3793 min · μmol · L−1 ; P < 0.0001 ) , but there was no significant difference in time taken to reach the maximal concentration ( 25 versus 47 min ) . Compared with the control situation , remifentanil  delayed gastric emptying in both postures . We conclude that remifentanil  delays gastric emptying and that this delay is not influenced by posture Background : Patients undergoing biliopancreatic diversion ( BPD )  may develop gastric ulcers , particularly within the first postoperative year . The prophylactic use of antisecretory compounds at the usual therapeutic doses , mainly conventional H2-receptor antagonists such as ranitidine , may reduce the incidence of this complication , which occurs in ∼5 % of patients after BPD . Methods : The authors measured the plasma concentrations of ranitidine ( 300 mg orally ) in obese patients , before and 8 months after BPD , and in control subjects of normal weight . The study included 11 obese patients undergoing BPD ( age 45 ± 14 years ; preoperative and postoperative weights 124 ± 21 and 92 ± 11 kg ) and 10 normal-weight subjects ( age 37 ± 13 years , weight 67 ± 9 kg ) .  Results : Postoperative ranitidine plasma concentrations showed only minor differences from preoperative levels , with slightly higher maximum concentrations occurring sooner . The mean area under the curve was on the average 30 % higher than preoperatively . All parameters , however , were similar to those in control subjects . Conclusions : BPD per se does not greatly affect the pharmacokinetic behavior of ranitidine , and therefore a conventional dosage regimen appears adequate for the prophylaxis and therapy of gastric ulcers associated with this operation STUDY OBJECTIVE The extended-release ( ER ) form of venlafaxine is preferred because of improved patient adherence , but the immediate-release ( IR ) form is frequently used after Roux-en-Y gastric bypass ( RYGB ) surgery because of concerns for malabsorption . The objective of this study was to determine whether a statistically significant and predictable change in the bioavailability of venlafaxine ER  capsules occurs after RYGB . DESIGN Prospect i ve nonblinded single-dose pharmacokinetic study . SETTING Clinical research unit at a large tertiary care medical practice . PATIENTS Ten adult pre-bariatric surgery patients who met the criteria for noncomplicated RYGB were enrolled and served as their own controls . INTERVENTIONS Patients were administered one venlafaxine ER 75-mg capsule at two visits-the first visit at least 1 week before undergoing RYGB and the second visit 3 - 4 months after RYGB . Blood sample s were collected at predetermined intervals over 48 hours after each dose , and the pharmacokinetics of venlafaxine  were measured . MEASUREMENTS AND MAIN RESULTS Plasma levels of venlafaxine and its primary metabolite , O-desmethylvenlafaxine ( ODV ) , were compared at baseline and 3 - 4 months after RYGB . The areas under the serum concentration-time curves from 0 - 24 hours ( AUC0 - 24 ) for venlafaxine ( mean ± SD 734 ± 602 vs 630 ± 553 ng·hr/ml , p=0.22 ) and ODV ( mean ± SD 894 ± 899 vs 1083 ± 972 ng·hr/ml , p=0.07 ) were similar before and after RYGB . Using a bioequivalence approach , differences in pre-RYGB and post-RYGB values of AUC0 - 24 , peak serum concentration , and time to peak serum concentration were not statistically significant for either venlafaxine or ODV . CONCLUSION This study suggests that RYGB does not significantly alter the amount of venlafaxine or its active metabolite , ODV , absorbed from a venlafaxine ER capsule or the time over which it is absorbed WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Numerous cocktails using concurrent administration of several cytochrome P450 ( CYP ) isoform-selective probe drugs have been reported to investigate drug-drug interactions in vivo . * This approach has several advantages : characterize the inhibitory or induction potential of compounds in development toward the CYP enzymes identified in vitro in an in vivo situation , assess several enzymes in the same trial , and have complete in vivo information about potential CYP-based drug interactions . WHAT THIS STUDY ADDS * This study describes a new cocktail containing five probe drugs that has never been published . * This cocktail can be used to test the effects of a new chemical entity on multiple CYP isoforms in a single clinical study : CYP1A2 ( caffeine ) , CYP2C9 ( warfarin ) , CYP2C19 ( omeprazole ) , CYP2D6 ( metoprolol ) , and CYP3A ( midazolam ) and was design ed to overcome potential liabilities of other reported cocktails . AIMS To assess the pharmacokinetics ( PK ) of selective substrates of CYP1A2 ( caffeine ) , CYP2C9 ( S-warfarin ) , CYP2C19 ( omeprazole ) , CYP2D6 ( metoprolol ) and CYP3A ( midazolam ) when administered orally and concurrently as a cocktail relative to the drugs administered alone . METHODS This was an open-label , single-dose , r and omized , six-treatment six-period six-sequence William 's design study with a wash-out of 7 or 14 days . Thirty healthy male subjects received 100 mg caffeine , 100 mg metoprolol , 0.03 mg kg(-1 ) midazolam , 20 mg omeprazole and 10 mg warfarin individually and in combination ( cocktail ) . Poor metabolizers of CYP2C9 , 2C19 and 2D6 were excluded . Plasma sample s were obtained up to 48 h for caffeine , metoprolol and omeprazole , 12 h for midazolam , 312 h for warfarin and the cocktail . Three different vali date d liquid chromatography t and em mass spectrometry methods were used . Noncompartmental PK parameters were calculated . Log-transformed C(max ) , AUC(last ) and AUC for each analyte were analysed with a linear mixed effects model with fixed term for treatment , sequence and period , and r and om term for subject within sequence . Point estimates ( 90 % CI ) for treatment ratios ( individual/cocktail ) were computed for each analyte C(max ) , AUC(last ) and AUC . RESULTS There was no PK interaction between the probe drugs when administered in combination as a cocktail , relative to the probes administered alone , as the 90 % CI of the PK parameters was within the prespecified bioequivalence limits of 0.80 , 1.25 . CONCLUSION The lack of interaction between probes indicates that this cocktail could be used to evaluate the potential for multiple drug-drug interactions in vivo STUDY OBJECTIVES To evaluate the effect of  Roux-en-Y gastric bypass surgery ( RYGB ) on the pharmacokinetics of midazolam ( a CYP3A4 substrate ) and digoxin ( a P-glycoprotein substrate ) . DESIGN Prospect i ve , nonblinded , longitudinal , single-dose pharmacokinetic study in three phases : presurgery baseline and postoperative assessment s at 3 and 12 months . PATIENTS Twelve obese patients meeting current st and ards for bariatric surgery . MEASUREMENTS AND MAIN RESULTS At each study visit , patients received a single dose of oral digoxin and midazolam at 8 a.m. Blood sample s were collected at regular intervals for 24 hours after dosing . Continuous 12-lead electrocardiogram ( EKG ) , heart rate , blood pressure , and respiratory rate were monitored , and pharmacokinetic parameters from the three visits were compared . The peak plasma concentration ( Cmax ) of midazolam increased by 66 % and 71 % at 3- and 12-month post-RYGB ( p=0.017 and p=0.001 , respectively ) , whereas the median time to peak concentration ( Tmax ) was reduced by 50 % . The mean Cmax for 1'-hydroxymidazolam increased by 87 % and 80 % at 3 and 12 months ( p=0.001 and p<0.001 , respectively ) . However , neither the area under the concentration-time curve ( AUC ) for midazolam nor the metabolite-to-parent AUC ratio changed significantly over time . For digoxin , the median Tmax decreased from 40 minutes at baseline to 30 and 20 minutes at 3 and 12 months , respectively . The mean AUC for digoxin , heart rate , and EKG patterns were similar across the three study phases . CONCLUSION Contemporary proximal RYGB increases the rate of drug absorption without significantly changing the overall exposure to midazolam and digoxin . The Cmax of a CYP3A4 substrate with a high extraction ratio was substantially increased after RYGB OBJECTIVE Morbidly obese patients frequently present with mood and anxiety disorders , which are often treated with serotonin reuptake inhibitors ( SRIs ) . Having observed that patients treated with SRIs frequently relapse after Roux-en-Y gastric bypass surgery , the authors sought to assess whether SRI bioavailability is reduced postoperatively . METHOD Twelve gastric bypass c and i date s treated with an SRI for primary mood or anxiety disorders were studied prospect ively . Timed blood sample s for  SRI plasma levels were drawn for pharmacokinetic studies before surgery and 1 , 6 , and 12 months afterward . Maximum concentration , time to maximum concentration , and area under the concentration/time curve ( AUC ) were determined . RESULTS In eight of the 12 patients , AUC values 1 month after surgery dropped to an average of 54 % ( SD=18 ) of preoperative levels ( range=36%-80 % ) ; in six of these patients , AUC values returned to baseline levels ( or greater ) by 6 months . Four patients had an exacerbation of depressive symptoms , which resolved by 12 months in three of them . Three of the four patients had a reduced AUC level at 1 month and either gained weight or failed to lose weight between 6 and 12 months . Normalization of the AUC was associated with improvement in symptom scores . CONCLUSIONS Patients taking SRIs in this study were at risk for reduced drug bioavailability 1 month after Roux-en-Y gastric bypass . The authors recommend close psychiatric monitoring after surgery Context Anti-retroviral therapy ( ART ) dramatically reduced AIDS development , thus enabling patients to live as long as the general population . New challenges have emerged particularly cardiometabolic diseases and weight gain , with some HIV patients seeking bariatric surgery ( BS ) . However , BS outcomes during HIV remain poorly described , with scarce data on ART pharmacokinetic post-BS . Objective Describing sleeve gastrectomy  ( SG ) results in HIV patients in terms of ART pharmacokinetic , HIV control , weight loss , and metabolic outcomes . Design , Setting , and Patients Prospect i ve study of HIV patients undergoing SG in a referral academic center , with at least 6 months follow-up . Main Outcome Measure Clinical and biological parameters , HIV medical history , and ART pharmacokinetics were gathered before and post-SG . Results Seventeen patients ( mean BMI = 44.2 ± 5.7 kg m−2 ) and major obesity-related diseases ( 47 % type-2 diabetes , 64 % obstructive sleep apnea , 70 % hypertension ) underwent SG during a mean 2 years of follow-up . They displayed an average of 20 % reduction of initial BMI and improved body composition , similarly to obese non-HIV patients . SG improved metabolic status . All patients had undetectable viral load before BS . Upon HIV follow-up , 12 patients had undetectable viral load with correct ART kinetic parameters ( 3 and 6 months ) ; 4 displayed detectable viral load along with significant decrease in raltegravir and atazanavir treatment exposure , leading to ART change with subsequent undetectable viral load ; and 1 had persistent detectable viral load despite ART change . Conclusions SG seems effective and safe in obese HIV patients . However , ART treatment should be monitored post-SG to control HIV infection . We suggest that some ART should be adapted before SG conjoints with infectious disease specialists BACKGROUND Weight loss is associated with short-term amelioration and prevention of metabolic and cardiovascular risk , but whether these benefits persist over time is unknown . METHODS The prospect i ve , controlled Swedish Obese Subjects Study involved obese subjects who underwent gastric surgery and contemporaneously matched , conventionally treated obese control subjects . We now report follow-up data for subjects ( mean age , 48 years ; mean body-mass index , 41 ) who had been enrolled for at least 2 years ( 4047 subjects ) or 10 years ( 1703 subjects ) before the analysis ( January 1 , 2004 ) . The follow-up rate for laboratory examinations was 86.6 percent at 2 years and 74.5 percent at 10 years . RESULTS After two years , the weight had increased by 0.1 percent in the control group and had decreased by 23.4 percent in the surgery group ( P<0.001 ) . After 10 years , the weight had increased by 1.6 percent and decreased by 16.1 percent , respectively ( P<0.001 ) . Energy intake was lower and the proportion of physically active subjects higher in the surgery group than in the control group throughout the observation period . Two- and 10-year rates of recovery from diabetes , hypertriglyceridemia , low levels of high-density lipoprotein cholesterol , hypertension , and hyperuricemia were more favorable in the surgery group than in the control group , whereas recovery from hypercholesterolemia did not differ between the groups . The surgery group had lower 2- and 10-year incidence rates of diabetes , hypertriglyceridemia , and hyperuricemia than the control group ; differences between the groups in the incidence of hypercholesterolemia and hypertension were undetectable . CONCLUSIONS As compared with conventional therapy , bariatric surgery appears to be a viable option for the treatment of severe obesity , result ing in long-term weight loss , improved lifestyle , and , except for hypercholesterolemia , amelioration in risk factors that were elevated at baseline Two established caffeine-based urinary methods for measuring CYP1A2 activity were compared with each other , and also with the systemic clearance of caffeine which served as a st and ard of reference for such activity . Following a st and ardized dose , caffeine ( 137X ) and its metabolites were measured in urine and plasma of 39 healthy subjects . The measurements allowed determinations of : ( 1 ) systemic caffeine clearance ( CL(caff ) ) ; ( 2 ) the caffeine metabolite ratio ( AFMU + 1X + 1U)/17U determined in an overnight-urine specimen and referred to as CMR , and ( 3 ) the ratio ( 17X + 17U)/137X measured in urine collected between 4 and 5 h after caffeine intake and referred to as PCUR for ' paraxanthine-caffeine urinary ratio ' . The PCUR showed a bimodal distribution and a relatively wide variation , CL(caff ) and CMR were both normally distributed . The correlation between CL(caff ) and CMR was r = 0.77 ( p < 0.001 ) , between CLcaff and PCUR r = 0.46 ( p < 0.01 ) , and between CMR and PCUR r = 0.40 ( p < 0.02 ) . The difference between the correlation coefficients 0.77 and 0.46 was statistically significant ( z-test ; p < 0.05 ) . The well established decrease of caffeine metabolism by oral contraceptive use was observed with both CL(caff ) and CMR but not with PCUR . Examination of possible explanations for the differences between PCUR and CMR led to the finding of a correlation between PCUR and the renal clearance of caffeine ( CLr ) with r = -0.47 ( p < 0.01 ) . Further scrutiny demonstrated that a bimodal or non-normal frequency distribution as shown by PCUR was also shown by CLr and by urine flow rate . ( ABSTRACT TRUNCATED AT 250 WORDS Background and Objectives Obesity and opioid use for chronic pain in obese individuals are both important public health concerns . The pharmacokinetics of oral morphine after Roux-en-Y gastric bypass ( RYGB ) are unknown . Therefore , we aim ed to study the pharmacokinetics of oral morphine in morbidly obese patients before and after RYGB surgery , to identify the effects of RYGB and the subsequent reversal of morbid obesity on the pharmacokinetic parameters of morphine . Methods The pharmacokinetics of oral morphine  ( 30 mg ) were studied in 30 obese patients before ( Visit 1 ) and then 7–15 days ( Visit 2 ) and 6 months ( Visit 3 ) after RYGB . A population pharmacokinetic model was used to describe the time course of the plasma morphine concentration , to study the effect of RYGB on morphine pharmacokinetics and to estimate inter-patient variability . Results The oral morphine time to maximum plasma concentration ( tmax ) was twofold lower and maximum plasma concentration ( Cmax ) was 1.7 times higher at Visit 2 , and tmax was 7.5 times lower and Cmax 3.3 times higher at Visit 3 than at Visit 1 . The mean oral morphine area under the plasma concentration – time curve ( AUC ) increased significantly ( 1.55-fold ) between Visits 1 and 3 . Changes in body mass index ( BMI ) after RYGB were clearly associated with decreased apparent oral morphine clearance and apparent central and peripheral morphine volumes of distribution . None of the other anthropometric parameters explained the inter-subject variability in morphine exposure better than BMI . Conclusion RYGB and the BMI reduction that followed it dramatically increased the rate of morphine absorption and slightly increased morphine exposure . The dose of immediate-release forms of morphine may be divided in obese patients after RYGB to prevent adverse events due to early and high morphine plasma peaks The biological effects of a new synthetic progestagen , Org 2969 ( 13-ethyl-11-methylene-18,19-dinor-17 alpha-pregn-4-en-20-yn-17-ol ) were studied in healthy normally menstruating women . Two of them were given 0.125 mg , five 0.060 mg and two 0.030 mg of Org 2969 daily on days 1 - 20 during one menstrual cycle . Serum levels of follicle stimulating hormone , luteinizing hormone , progesterone and oestradiol were analyzed on days 8 - 23 in order to evaluate the function of the hypophyseal-ovarian axis . The serum concentrations of aspartate amino transferase , alanine amino transferase , alkaline phosphatase , gamma glutamyl transpeptidase and bilirubin were determined to evaluate possible side effects on live function on days 8 , 15 and 23 . Serum cortisol was measured on days 8 and 23 . The basal body temperature was recorded daily during the whole cycle , and endometrium biopsies were taken on days 21 or 22 of the cycle . All sample s were taken similaryl during the treatment cycle and the preceding control cycle . According to the hormone determinations , all the treatment cycles were anovulatory except in one woman receiving the lowest dose . The treatment led to decreased spinnbarkeit , arborization and sperum penetration in the cervical mucus . Liver function tests and serum cortisol remained unchanged during the treatment To investigate whether  Roux‐en‐Y gastric bypass ( RYGB )  affects oral desogestrel ( etonogestrel ) pharmacokinetics BACKGROUND Thromboembolic disease is a potentially serious complication in bariatric surgery patients . Direct oral anticoagulants ( DOAC ) have been investigated in orthopedic surgery patients .  DOAC data after bariatric surgery are still limited to the early postsurgical period . Whether postsurgical midterm adaptations due to anatomic and physiologic alterations influence drug pharmacology is currently not known . OBJECTIVE The aim of this study was to investigate the influence of weight loss and type of bariatric surgery on midterm postsurgical pharmacokinetic and pharmacodynamic parameters of rivaroxaban . SETTING University hospital . METHODS In this monocentric study , bariatric patients received a single oral dose of rivaroxaban ( 10 mg ) 6 to 8 months after sleeve gastrectomy ( SG ) or Roux-en-Y-gastric bypass ( RYGB ) . Pharmacokinetic and pharmacodynamic parameters were assessed and compared with prebariatric surgery results . RESULTS We included 6 RYGB and 6 SG patients .  Percent excess weight loss was 71.4 % ( interquartile range 56.4 , 87.9 ) in the SG group and 76.6 % ( 64.5 , 85.7 ) in the RYGB group . Rivaroxaban mean areas under the curve 6 to 8 months after the bariatric procedure ( 922.4 µg × h/L , coefficient of variation 43.2 ) were comparable to those measured preoperatively ( 952.6 µg × h/L , 16.8 ) . There was no relevant difference between the 2 surgical procedure groups . Rivaroxaban led to a decrease of prothrombin fragments F1 + 2 over 12 hours after oral intake confirming in vivo efficacy . CONCLUSIONS Significant weight loss and altered anatomy after RYGB and SG procedures do not appear to affect the pharmacokinetics and pharmacodynamics of prophylactic rivaroxaban . A single dose of Rivaroxaban was well tolerated and considered safe in this trial Background Bariatric surgery leads to several anatomo-physiological modifications that may affect pharmacokinetic parameters and consequently alter the therapeutic effect of drugs , such as antibiotics . The pharmacokinetics of oral amoxicillin after Roux-en-Y gastric bypass ( RYGB ) surgery is unknown . Objectives The objective of this study was to evaluate the impact of bariatric surgery on the pharmacokinetics of  amoxicillin . Methods This study was performed as a r and omized , open-label , single-dose clinical trial , with two periods of treatment , in which obese subjects ( n = 8) received an amoxicillin 500 mg capsule orally before and 2 months after the RYGB surgery . The  amoxicillin plasma concentration was determined by liquid chromatography coupled to mass spectrometry ( LC-MS/MS ) . Results After the surgery , the mean weight loss was 17.03 ± 5.51 kg , and mean body mass index ( BMI ) decreased from 46.21 ± 2.82 to 38.82 ± 3.32 kg/m2 . The mean amoxicillin area under the plasma concentration versus time curve from time zero to the time of the last quantifiable concentration ( AUC0–tlast ) increased significantly ( 3.5-fold ) ; the maximum plasma concentration ( Cmax ) increased 2.8-fold after the bariatric surgery . No correlation was found between amoxicillin absorption , BMI , and weight loss percentage . Conclusion The alterations observed in the amoxicillin pharmacokinetics suggest that obese subjects included in this trial had a substantially increase in amoxicillin systemic exposure after RYGB surgery . However , despite this increase , its exposure was lower than the values reported for non-obese volunteers . Trial Registration Identifiers : AIMS The anticoagulant rivaroxaban is an oral , direct Factor Xa inhibitor for the management of  thromboembolic disorders .  Metabolism and excretion involve cytochrome P450 3A4 ( CYP3A4 ) and 2J2 ( CYP2J2 ) , CYP-independent mechanisms , and P-glycoprotein ( P-gp ) and breast cancer resistance protein ( Bcrp ) ( ABCG2 ) . METHODS The pharmacokinetic effects of substrates or inhibitors of CYP3A4 , P-gp and Bcrp ( ABCG2 ) on rivaroxaban were studied in healthy volunteers . RESULTS Rivaroxaban did not interact with midazolam ( CYP3A4 probe substrate ) . Exposure to  rivaroxaban when co-administered with midazolam was slightly decreased by 11 % ( 95 % confidence interval [ CI ] -28 % , 7 % ) compared with rivaroxaban alone . The following drugs moderately affected  rivaroxaban  exposure , but not to a clinical ly relevant extent : erythromycin ( moderate CYP3A4/P-gp inhibitor ; 34 % increase [ 95 % CI 23 % , 46 % ] ) , clarithromycin ( strong CYP3A4/moderate P-gp inhibitor ; 54 % increase [ 95 % CI 44 % , 64 % ] ) and fluconazole ( moderate CYP3A4 , possible Bcrp [ ABCG2 ] inhibitor ; 42 % increase [ 95 % CI 29 % , 56 % ] ) . A significant increase in  rivaroxaban exposure was demonstrated with the strong CYP3A4 , P-gp/Bcrp ( ABCG2 ) inhibitors ( and potential CYP2J2 inhibitors ) ketoconazole ( 158 % increase [ 95 % CI 136 % , 182 % ] for a 400 mg once daily dose ) and ritonavir ( 153 % increase [ 95 % CI 134 % , 174 % ] ) . CONCLUSIONS Results suggest that rivaroxaban may be co-administered with CYP3A4 and /or P-gp substrates/moderate inhibitors , but not with strong combined CYP3A4 , P-gp and Bcrp ( ABCG2 ) inhibitors ( mainly comprising azole-antimycotics , apart from fluconazole , and HIV protease inhibitors ) , which are multi-pathway inhibitors of rivaroxaban clearance and elimination AIMS The aim of the present study was to evaluate the disposition of metoprolol after oral administration of an immediate and controlled-release formulation before and after Roux-en-Y gastric bypass ( RYGB ) surgery in the same individuals and to vali date a physiologically based pharmacokinetic ( PBPK ) model for predicting oral bioavailability following RYGB . METHODS A single-dose pharmacokinetic study of metoprolol tartrate 200 mg immediate release and controlled release was performed in 14 volunteers before and 6 - 8 months after RYGB . The observed data were compared with predicted results from the PBPK modelling and simulation of metoprolol tartrate immediate and controlled-release formulation before and after RYGB . RESULTS After administration of metoprolol immediate and controlled release , no statistically significant difference in the observed area under the curve ( AUC(0 - 24 h ) ) was shown , although a tendency towards an increased oral exposure could be observed as the AUC(0 - 24 h ) was 32.4 % [ 95 % confidence interval ( CI ) 1.36 , 63.5 ] and 55.9 % ( 95 % CI 5.73 , 106 ) higher following RYGB for the immediate and controlled-release formulation , respectively . This could be explained by surgery-related weight loss and a reduced presystemic biotransformation in the proximal gastrointestinal tract . The PBPK values predicted by modelling and simulation were similar to the observed data , confirming its validity . CONCLUSIONS The disposition of metoprolol from an immediate-release and a controlled-release formulation was not significantly altered after RYGB ; there was a tendency to an increase , which was also predicted by PBPK modelling and simulation
target: In the case of the majority of studied drugs , an increased absorption rate was observed early after RYGBP .
  The effect on systemic exposure allows for a low degree of extrapolation , including between drugs subjected to the same major metabolic and transporter pathways .
background: Anatomical changes in the gastrointestinal tract and subsequent weight loss may influence drug disposition and thus drug dosing following bariatric surgery .
  This review systematic ally examines the effects of bariatric surgery on drug pharmacokinetics , focusing especially on the mechanisms involved in restricting oral bioavailability .