W1404 Metoclopramide Metabolism: Identification of Metoclopramide Metabolites in Humans

AGA Abstracts

whole stomach. WMC Motility Index (MI; mmHg*s)/min) was calculated for 15 minute periods centered at WMC gastric emptying. Results are reported mean ±SEM. Results: The t-1/2 for LNM was similar to EWS (1.41±0.11 vs 1.52±0.08 hours; p=0.275) and the two were significantly correlated (r=0.527; p=0.017). There were time related differences in the emptying of the LMN compared to EWS. In the first hour, gastric retention of EWS was greater than LNM (74±3% vs 64±3%; p=0.014). At 1.5, 2 and 2.5 h there was no difference in retention of EWS and LNM. In the later time points of the study, retention of EWS was less than LNM (8±2% vs 15±2% at 3 hr; p=0.022, 2±1% vs 6±2% at 4 hr; p=0.012). Regionally, movement of the meal from the proximal to the distal stomach differed between the meals: % of meal in proximal stomach for EWS was greater than LNM at 0.5 h (61±3% vs 34±4%; p=0.001). The WMC gastric emptying time trended slower for LNM (209±13 min vs 236±13 min; p=0.115). The WMC MI was similar for EWS and LMN with each displaying an increase in MI from 30 min to the 15 min period prior to emptying (EWS: 64±15 to 116±19; p=0.007 and LNM: 79±15 to 134±24; p=0.035). Conclusions: The LNM Ensure Plus can serve as an alternative meal to the conventional solid EWS for GES. There are, however, temporal and regional differences between gastric emptying of EWS meal and LNM. These differences are likely due to need for trituration of the EWS solids with early retention in the proximal stomach. LNM, on the other hand, leaves the proximal stomach without a lag phase but takes longer to empty from the distal stomach possibly due to higher fat content.

W1403 Prevalence of Gastroparesis in Symptomatic Type 1 Diabetics Using 13COctanoic Acid Breath Test and Relationship to Dyspeptic Symptoms Catalin Sfarti, Anca Trifan, Camelia Cojocariu, Catalin I. Hutanasu, Ana Maria Singeap, Carol Stanciu Background and Aim: Gastroparesis and/or dyspeptic symptoms occur in around 50% of type 1 diabetic patients. The relationship between diabetic gastroparesis and dyspeptic symptoms was less evaluated. The aim of our study was to evaluate the prevalence of gastroparesis in patients with type 1 diabetes using 13C-octanoic acid breath test (13COBT) and the relationship between dyspeptic symptoms and gastric emptying. Material and methods. Gastric emptying of solids was evaluated prospectively in euglycemic conditions in 69 type 1 diabetic patients (male/female: 36/33; mean age 49.5 years ± 14.2 years; mean duration of diabetes 20.4 ± 8.2 years) and 40 healthy volunteers (male/female 17/23; mean age 34.3 years ± 16.1 years) using 13C-OBT. Dyspeptic symptoms, autonomic nerve function and Helicobacter pylori (H. pylori) status were assessed. Results. Solid gastric emptying was significantly slower in diabetic patients (T1/2=125.36 min ± 31.5min) than in healthy subjects (T1/2=88.5min ± 27.3 min) (p<0.05). Delayed gastric emptying was significantly slower in diabetic female than in diabetic male patients (p<0.05). Body mass index (BMI) was the only independent predictor for delayed solid gastric emptying in a logistic regression model testing HbA1c, age, diabetes duration, H. pylori status, peripheral neuropathy, retinopathy, nephropathy, and autonomic neuropathy. Postprandial fullness and epigastric discomfort were associated with delayed gastric emptying. Conclusions. We found that 33.7% of type 1 diabetic patients had delayed gastric emptying that correlates with female gender, increased BMI, postprandial fullness and epigastric discomfort.

W1401 Mirtazapine Partially Blocks the Inhibitory Effects of Rectal Distention on Gastric Tone and Gastric Accommodation in Dogs Yong Lei, Jiande Chen Background and Aims: Antidepressants are commonly used in treating functional gastrointestinal (GI) diseases. However their effects on GI motility are relatively unknown. The aim of this study was to investigate the effect of Mirtazapine, a new antidepressant, on rectal distention (RD)-induced gastric dysmotility in dogs. Methods: Six healthy dogs implanted with a gastric cannula were studied in 4 randomized sessions: control, Mirtazapine, RD, and RD+Mirtazapine. Gastric tone was recorded using a barostat for 30min in the fasting state and 30min after a liquid meal (237ml Boost) in the sessions without RD, and for 60 min in the fasting state and 60 min after the same liquid meal in the sessions with RD (100ml air) that was performed during the last 30-min fasting period and first 30-min postprandial period. Mirtazapine (45mg) was administrated orally 1.5 hrs before the recording. Gastric accommodation was defined as the difference in gastric volume between fed and fasting states. Animal behaviors suggestive of discomfort were recorded in each session. Results: 1) Mirtazapine had no effects on gastric tone or gastric accommodation in the normal physiological condition (no RD). 2) RD significantly inhibited gastric tone and reduced gastric accommodation; whereas Mirtazapine partially blocked the inhibitory effects of RD on gastric tone and gastric accommodation. The RD-induced increase in gastric volume in the fasting state was 253.6 ± 61.1% without Mirtazapine and 97.8 ± 23.1% with Mirtazapine (P=0.03). Gastric accommodation was 149.4 ± 29.8ml with RD and 290.9 ± 45.7ml with RD+Mirtazapine (P=0.012); (3) The animal behavioral score was 9.5 ± 1 during RD and reduced to 3.3 ± 0.6 (P=0.001) during RD with Mirtazapine. Conclusions: Mirtazapine has no effects on gastric tone or gastric accommodation under the normal physiological condition but partially blocks the inhibitory effects of RD on gastric tone and gastric accommodation. Mirtazapine seems to have an antagonizing effect on inhibitory rectogastric reflex.

W1404 Metoclopramide Metabolism: Identification of Metoclopramide Metabolites in Humans Upendra Argikar, Javier Gomez, Din Ung, Henry P. Parkman, Swati Nagar Metoclopramide (MCP), the only FDA-approved drug to treat patients with gastroparesis, reduces symptoms but is associated with both acute and chronic side effects. While MCP has been prescribed for decades, its metabolism in humans is poorly understood. Better understanding of MCP metabolism will allow better optimization of its efficacy and side effect profile. Aim: The aim of the study was to better understand human MCP metabolism. We therefore identified MCP metabolites in human liver tissue and in urine of healthy human volunteers. Methods: In Vitro incubations were carried out in human liver microsomes (HLM) to characterize metabolism via cytochromes P450 (CYPs) and uridine diphosphoglucuronosyltransferases (UGTs), and in human liver cytosol (HLC) for metabolism via sulfotransferases (SULTs). Incubations were analyzed for metabolite formation with HPLC and mass spectrometry with a specific and sensitive LC-MSn assay. For In Vivo metabolism, an oral 20 mg MCP dose was administered to 8 healthy male volunteers, followed by 24 hour urine collection. Urine samples were analyzed for MCP metabolites on a Thermo Orbitrap® mass spectrometer. Results: Ten MCP metabolites were detected In Vitro, of which 5 metabolites were confirmed in human urine samples. Both ‘phase I' oxidative and ‘phase II' conjugative metabolites were detected. In Vitro studies in HLM revealed the following metabolites: two ether glucuronides (M6, M7) possibly on the phenyl ring, and N-glucuronide (M8), a nitroso (M9), and a carbamic acid (M10). Metabolites M6 - M10 have not been reported previously. The 5 metabolites of MCP identified both In Vitro and In Vivo were: an N-O-gluucuronide (M1), an N-sulfate (M2), an oxidative de-aminated metabolite (M3), a hydroxylated metabolite (M4), and a desethyl metabolite (M5). Of these, metabolites M2, M3 and M5 have been reported in humans. However, to our knowledge, metabolites M1 and M4 have not been previously reported. There was marked inter-subject variability in the formation of metabolites: M2 urinary levels varied 22-fold while M5 levels varied 16-fold among 8 subjects. Conclusions: Five MCP urinary metabolites were identified, with 5 additional metabolites formed In Vitro. Seven of these 10 metabolites have not previously been reported. There was marked inter-individual variability in the urinary levels of all MCP metabolites. One possible explanation for this is pharmacogenetic variability in enzymes, especially CYPs. Metabolites detected In Vitro but not In Vivo could be formed in humans and eliminated via biliary excretion. MCP metabolites are thought to be inactive, but whether they contribute to drug-related toxicity is unknown.

W1402 Infections in Patients With Symptomatic Exacerbations of Gastroparesis. Jessica Abellard, Priyanka Sachdeva, Henry P. Parkman Hospitalizations for gastroparesis have been increasing in the United States over the last decade (Wang 2008). We have previously reported that bacterial infections are associated with gastroparesis exacerbations (Uppalapati 2009). Viruses have also been implicated in idiopathic gastroparesis (Naftali 2007). The aim of this study was to investigate whether infections, either bacterial or viral, are associated with exacerbations of gastroparesis leading to hospital admission. Furthermore, we wished to explore whether the inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), may help identify patients with infections. Methods: Patients with gastroparesis requiring hospital admission for an exacerbation were interviewed about their symptoms of gastroparesis and infections. Laboratory tests included complete blood count, ESR, CRP, and urinalysis. Viral titers were drawn for cytomegalovirus (CMV), Epstein Barr virus (EBV), Herpes Zoster, and Herpes Simplex I and II. Results: 86 patients with a history of gastroparesis required admission to Temple University Hospital for an exacerbation of their symptoms from July 2007 to September 2009. Mean age was 35.3 years (range 18-68), 67 were females, and 22 were diabetic. Sixteen (18.6%) patients had a documented bacterial infection (urinary tract infection in 5 patients, abscess in 4, PICC line infection in 4, cellulitis/skin lesions in 2, and pneumonia in 1). Of the 16 patients with a positive bacterial infection, bacteremia was present in 6 patients (2 abscesses, 2 PICC line infections, 1 urinary tract infection, and 1 pneumonia). Acute viral infections, as evidenced by positive IgM titer, were present in five (5.8%) patients: 2 CMV, 2 EBV, and 1 patient both EBV and CMV. IgG titers revealed past exposure to CMV in 29 patients, EBV in 59, H Zoster in 70, H Simplex I in 34, H Simplex II in 14 patients. Overall, 44 patients had an elevated ESR level while 18 patients had an elevated CRP. Elevation of inflammatory markers were associated with the presence of infection: bacterial infection (ESR: p=0.071; CRP: p<0.001); viral infection (ESR: p=0.057; CRP: p= 0.01). Conclusions: Infections are associated with exacerbations of symptoms of gastroparesis. In this series, bacterial infections were present in 19% of patients admitted for gastroparesis exacerbations. A minority of patients (5.8%) had positive IgM viral titers suggesting an acute viral infection. The inflammatory markers, ESR and CRP, are elevated in the patients with infections, both bacterial and viral. Careful assessment for infections is warranted in patients admitted for gastroparesis exacerbations.

AGA Abstracts

W1405 New Surgery for Gastroparesis-Enterra Plus Pyloroplasty: Its Efficacy in Different Etiologies of Gastroparesis Irene Sarosiek, Katherine Roeser, Jameson Forster, Reza A. Hejazi, Jerzy Sarosiek, Richard McCallum Introduction: Improvement of gastroparesis (GP) symptoms in a drug-refractory population of patients treated with gastric electrical stimulation (GES) with the Enterra device is well established. The unpredictable effect of GES on accelerating the rate of gastric emptying (GET) remains a limiting factor in the broad acceptance of this device. Aim: To evaluate the long term advantage of adding surgical pyloroplasty (PP) to GES therapy for improvement of GET as well as control of symptoms in 3 etiological groups of GP patients (diabetes-DM, idiopathic- ID, post-vagotomy-P-V). Methods: 26 prokinetic and antiemetic refractory GP patients (8-DM, 5-ID, 13P-V) 8M, mean age 43 (26-73) mean weight 158lbs (102-245) with mean duration of GP of 3 years (1-8 )underwent implantation of the Enterra GES system with the addition of a surgical PP performed by a single surgeon. Total GP symptoms scores (TSS) assessing severity (S) and frequency (F) of nausea, vomiting, early satiety, fullness, epigastric pain, were obtained by using 5-point Likert scale at baseline and at last follow, which was up to 18 months after receiving both therapies. The standardized 4-hour GET was conducted before surgery and at F/U visits with GP defined as >10% retention of isotope at 4 hrs. Changes in weight and days of hospitalization were also captured. Results: All 3 groups maintained their mean weight, and hospitalization rates were reduced significantly in all groups from a mean of 28 days in the year preceding surgery to 2 at F/U. All results

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