Identification of domperidone metabolites in plasma and urine of gastroparesis patients with LC-ESI-MS/MS.

Domperidone is a prokinetic agent used to treat gastroparesis. Previous studies reported oxidative metabolites of domperidone, detected by radiometric high-performance liquid chromatography or single quadrupole mass spectrometric techniques. Our aim was to identify domperidone Phase I and Phase II metabolites using liquid chromatography combined with electrospray ionization-enabled tandem mass spectrometry. Domperidone metabolites were identified in the plasma and urine of 11 gastroparesis patients currently being treated with domperidone. In addition, oxidative and conjugative metabolites of domperidone were characterized in human liver subcellular fractions. Seven metabolites were detected in vivo. Domperidone was metabolized to two mono-hydroxylated metabolites (M1 and M2), a de-alkylated metabolite (M5) and a di-hydroxylated metabolite (M7). The mono-hydroxylated metabolites were further glucuronidated to M8, M9 and sulfated to M11. To the best of our knowledge, M7, M8, M9 and M11 have not been reported previously. Five additional metabolites were identified in vitro in human subcellular fractions which comprise two additional mono-hydroxylated metabolites (M3 and M4), an alcohol metabolite (M6) possibly formed from an aldehyde intermediate, and other conjugative metabolites (M10 and M12). M6, M10 and M12 have not been characterized previously. In total, 12 domperidone metabolites including 7 new metabolites were identified in the present study. These results allow a better understanding of domperidone disposition in humans.

Clinical response and side effects of metoclopramide: associations with clinical, demographic, and pharmacogenetic parameters.

OBJECTIVES: Metoclopramide is associated with variable efficacy and side effects when used in the treatment of gastroparesis. AIM: To determine associations of clinical and pharmacogenetic parameters with response and side effects to metoclopramide in patients with upper gastrointestinal symptoms suggestive of gastroparesis. METHODS: Gastroparetic patients treated with metoclopramide were enrolled. Clinical parameters recorded were age, sex, weight, diabetic status, gastric emptying result, daily dose, effectiveness, and side effects. DNA was isolated from salivary samples; 20 single nucleotide polymorphisms were genotyped in 8 candidate genes (ABCB1, ADRA1D, CYP1A2, CYP2D6, DRD2, DRD3, HTR4, KCNH2). RESULTS: One hundred gastroparetic patients treated with metoclopramide participated. Dose averaged 33±16 mg/d for 1.1±1.7 years. Responders (53 of 100 patients) were older (48±15 vs. 38±11 y; P=0.0004) and heavier (body mass index of 28±7 vs. 25±7; P=0.0125). Efficacy was associated with polymorphisms in KCNH2 (rs1805123, P=0.020) and ADRA1D (rs2236554, P=0.035) genes. Side effects, occurred in 64 patients, were more common in females (83% vs. 64%; P=0.037), nondiabetics (77% vs. 47%; P=0.004), and patients with normal gastric emptying (41% vs. 17%; P=0.015). Side effects were associated with polymorphisms in CYP2D6 (rs1080985, P=0.045; rs16947, P=0.008; rs3892097, P=0.049), KCNH2 (rs3815459, P=0.015), and serotonin 5-HT4 receptor HTR4 gene (rs9325104, P=0.026). CONCLUSIONS: Side effects to metoclopramide were more common in nondiabetic patients with normal gastric emptying. Polymorphisms in CYP2D6, KCNH2, and 5-HT4 receptor HTR4 genes were associated with side effects, whereas polymorphisms in KCNH2 and ADRA1D genes were associated with clinical response. Clinical parameters and pharmacogenetic testing may be useful in identifying patients before treatment with metoclopramide to enhance efficacy and minimize side effects.

Gastric emptying scintigraphy: is four hours necessary?

INTRODUCTION: Recommendations for gastric emptying scintigraphy (GES) suggest imaging over 4 hours to better define gastroparesis. AIMS: To determine the value of defining delayed gastric emptying at time points earlier than 4 hours. METHODS: GES was performed with ingestion of a liquid egg white meal with imaging at 0, 0.5, 1, 2, 3, and 4 hours. Patients completed the Patient Assessment of Gastrointestinal Symptoms questionnaire immediately before GES. RESULTS: Of 1499 patients undergoing GES from September 2007 to January 2010 (76.2% were female, mean age of 45.5±0.5 y, 21.3% had diabetes, 9.5% had earlier gastric surgery), 160 (10.7%) had increased gastric retention at 1 hour (>90%), 404 (27%) had increased retention at 2 hours (>60%), 576 (38.4%) had increased retention at 3 hours (>30%), and 629 (42%) had increased retention at 4 hours (>10%). Gastric retention at 4 hours correlated with retention at 3 hours (r=0.890; P<0.001), 2 hours (r=0.738; P<0.001), and 1 hour (r=0.510; P<0.001). Symptoms correlated better with the gastric retention at later time points. The symptoms correlating with gastric retention at 4 hours included early satiety (r=0.170; P<0.01), vomiting (r=0.143; P<0.01), feeling excessively full after meals (r=0.123; P<0.01), and loss of appetite (r=0.122; P<0.01). CONCLUSIONS: Gastric retention at 4 hours correlates well with gastric retention at 3 hours, good at 2 hours, but only fair with gastric retention at 1 hour. Gastric retention at 1 hour may miss 36% of patients found to have delayed gastric emptying at 4 hours. Symptoms (early satiety, vomiting, feeling excessively full after meals, and loss of appetite) correlated better with the gastric retention at later time points.

Fatigue: a prevalent symptom in gastroparesis.

BACKGROUND: Fatigue is seen in many medical conditions. Patients with gastroparesis may complain of fatigue. AIM: The aim of this work is to first assess the prevalence and severity of fatigue in patients with gastroparesis, and secondly to correlate fatigue with symptoms, quality of life, and factors that may contribute to fatigue. METHODS: One hundred and fifty-six patients with gastroparesis filled out questionnaires including the fatigue assessment instrument (FAI), patient assessment of upper gastrointestinal symptom severity index, patient assessment of upper gastrointestinal disorders-quality of life and hospital anxiety, and depression scale to evaluate for fatigue, symptoms, quality of life, and depression. Gastric emptying test and laboratory studies for hemoglobin, glycosylated hemoglobin, thyroid function (TSH), and inflammatory markers (CRP and ESR) were obtained. RESULTS: Fatigue was reported by 93 % of patients. The mean total FAI score was 3.71 ± 0.2, with 51 % of patients having a score above 4, indicating severe fatigue. There were moderate correlations between fatigue and many symptoms of gastroparesis: upper abdominal discomfort (r = 0.446), upper abdominal pain (r = 0.422), loss of appetite (r = 0.329), bloating (r = 0.297), and abdominal distention (r = 0.265). Fatigue in patients using metoclopramide (3.5 ± 0.4) was similar to patients using domperidone (3.7 ± 0.5) or neither medicine (3.8 ± 0.3). Fatigue severity correlated with a decreased quality of life (r = -0.694, p < 0.001), increased depression (r = 0.339, p = 0.009), lower anxiety (r = -0.441, p < 0.001), and lower hemoglobin levels (r = -0.258, p = 0.005), but not to glycosylated hemoglobin, ESR, CRP, TSH, or gastric emptying. CONCLUSIONS: Fatigue is an important significant symptom in patients with gastroparesis with a high prevalence and severity. Fatigue is correlated with many symptoms of gastroparesis, low hemoglobin, depression, inflammation, decreased quality of life, but not to severity of delayed gastric emptying or to medication use.

Gastric emptying of solids and liquids for evaluation for gastroparesis.

BACKGROUND: Gastric emptying scintigraphy (GES) of solids is typically used to evaluate for gastroparesis. AIMS: The purpose of this study was to determine the value of simultaneously measuring gastric emptying of liquids and solids for assessing patients for delayed gastric emptying. METHODS: A total of 596 patients at our institution from September 2007 to January 2010 underwent GES with assessment of both solid and liquid gastric emptying. An EggBeaters® with jam sandwich meal radiolabeled with Tc-99 m was used for solid GES and water radiolabeled with In-111 for liquid GES. RESULTS: Inclusion criteria (no medications affecting gastric motility in 48 h prior to test; no prior gastric surgery) was met by 449 patients. Liquid gastric emptying was significantly correlated to solid gastric emptying: 30 min (r=0.652, P<0.001), 60 min (r=0.624, P<0.001) and 120 min (r=0.766, P<0.001). Interestingly, 60 patients, of which 57 were nondiabetic, had normal solid GES but delayed liquid emptying and represented 26% of the 228 patients with normal solid GES. Gastric retention of solids was mildly correlated with nausea, vomiting, loss of appetite, early satiety and feeling excessively full after meals. Gastric emptying of liquids was associated with early satiety and loss of appetite. CONCLUSIONS: Gastric emptying of liquids correlates well with gastric emptying of solids. When evaluating patients for gastroparesis, assessment of gastric emptying of liquids in addition to solids may help identify additional patients with delayed gastric emptying, particularly non-diabetic patients where 26% with normal solid emptying may have delayed emptying of liquids. Symptoms of gastroparesis, however, are primarily associated with delayed gastric emptying of solids.

Acute liver failure.

Acute liver failure is a rare but often catastrophic illness affecting the liver and multiple organ systems. Patients with acute liver failure require a multidisciplinary approach for adequate management. With improved critical care and the availability of liver transplantation, survival has significantly improved. Hepatic encephalopathy, cerebral edema and infections are the most common complications of acute liver failure. The evaluation requires a diligent search for a specific etiology of the liver failure, since certain causes may respond well to specific pharmacological therapies. Acetaminophen and non-acetaminophen drug-induced hepatotoxicity account for more than 50% of cases of acute liver failure. Assessment of prognosis frequently (at least on a daily basis) by using various prognostic tools, allows the treating team to decide whether or not to proceed with urgent liver transplantation. Artificial liver support devices are still in evaluation and not ready for use in clinical practice. While it is determined whether or not there is sufficient hepatic regeneration, the care of the patient with acute liver failure revolves around managing the dysfunction of multiple extra hepatic systems.