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T1270 Food Does Not Affect the Oral Bioavailability of Prucalopride
AGA Abstracts
and most (83%) participants thought that the response scales from none to very severe captured their symptom experience and were simple to use. All participants reported that the diary items captured their symptom experience with gastroparesis. Participants with diabetic or idiopathic gastroparesis reported similar symptoms and had comparable comprehension of the GCSI daily diary, indicating that the set of symptom items was relevant across different gastroparesis etiologies. Conclusions: The GCSI daily diary was relevant to patients with symptoms of gastroparesis. Together with extensive previous validation of the GCSI, this GCSI daily symptom diary has the characteristics to be a good patient reported outcome for evaluating the effectiveness of treatments in clinical trials for gastroparesis.
T1270 Food Does Not Affect the Oral Bioavailability of Prucalopride Vera J. Van de Velde, Jannie Ausma, Lieve Vandeplassche Background: Prucalopride (PRU), a dihydrobenzofurancarboxamide derivate, is a 5-HT4 receptor agonist with strong enterokinetic activity. PRU is currently developed for treatment of chronic constipation in adults. The recommended therapeutic dosage is 2 mg PRU o.d.; the formulation is a direct-compression tablet containing prucalopride succinate, equivalent to 2 mg prucalopride base. Objective: The present study investigated the effect of concomitant food intake on the oral bioavailability of PRU. Methods: Following a balanced, 2-way crossover randomization, 6 male and 8 female subjects were administered a 2-mg PRU tablet in fasting conditions and immediately after a high-fat, high-calorie breakfast. The washout period between drug doses was 2 weeks. Plasma concentrations of PRU were determined up to 96 h after each dose, using a validated radioimmunoassay with a lower limit of quantification of 0.1 ng/mL. Pharmacokinetic parameters were calculated using standard non-compartmental methods. Results: Pharmacokinetic parameters (mean ± SD) are summarized in the table below. There were no statistically significant differences between fasted and fed intake for any of the pharmacokinetic parameters. Mean treatment ratios and associated 90% confidence intervals of log-transformed Cmax (98-115%), AUClast and AUC∞ (both 91-101%) were well contained in the 80-125% equivalence range. Both treatments appeared to be safe, and reasonably well tolerated. Other than headache, the most frequently reported side-effects (diarrhoea, flatulence, nausea) in this population of healthy subjects were of gastro-intestinal origin, related to PRU's pharmacodynamic profile. Their incidence was similar for both treatments. Headache occurred more frequently when subjects were dosed in the fasting state. Conclusion: Food did not have an effect on the oral bioavailability of PRU. Rate and extent of absorption were not different after dosing to fasted subjects or after a high-fat, high calorie breakfast.
T1268 Pharmacologic Interaction of Domperidone and Erythromycin: MechanismBased Enzyme Inhibition of Domperidone Hydroxylation By Erythromycin in Human Liver Microsomes Din Ung, Henry P. Parkman, Swati Nagar The prokinetic drugs domperidone (DOM) and erythromycin (ERY) are used to treat patients with gastroparesis. In refractory patients with gastroparesis, they can be used in combination. DOM and ERY are metabolized by cytochrome P450 (CYP) 3A4, an enzyme known to be inhibited by ERY. Aim: The aim of this study examines the potential drug-drug interaction of DOM and ERY in pooled human liver microsomes (HLMs). Methods: Time- and concentration-dependent enzyme assays were performed in HLM to evaluate drug-drug interaction mediated by mechanism-based inactivation. CYP activity towards DOM was characterized in HLM pre-incubated with ERY at various concentrations (10 - 200 μM) and pre-incubation times (10 - 40 min). Pre-incubation mixtures consisted of 0.5 mg/ml HLM, NADPH-regenerating system, ERY, and 0.05 M potassium phosphate buffer (pH 7.4). After pre-incubation at 37°C, DOM was added to the mixture and further incubated for 30min. Reactions were terminated by addition of cold acetonitrile containing internal standard encainide. Samples were analyzed for DOM metabolites using a validated HPLC assay. Kinetics constants of inactivation were calculated graphically. Apparent rates of inactivation were estimated from slopes of a plot of the log of enzyme activity remaining after pre-incubation with respect to pre-incubation time. A double-reciprocal plot of the rates of inactivation against inhibitor concentration was used to obtain estimates of concentration required for half-maximal inactivation, KI, and for maximum rate of inactivation, kinact, from the x- and y-intercepts, respectively. Results: Addition of domperidone to HLM In Vitro preparations, resulted in domperidone along with three major and two minor metabolites of DOM being observed. ERY significantly inhibited the metabolism of DOM. The major metabolite of interest was 5-hydroxydomperidone, which displayed Michaelis-Menten kinetics with a Vmax = 0.53 ± 0.03 nmol/min/mg protein and Km = 53 ± 10 μM; data expressed as mean ± S.E., n = 3. A time- and concentration-dependent inhibition (i.e. reduced DOM metabolism) of 5hydroxydomperidone by ERY was observed in HLM. Estimates of inactivation kinetic constants were: KI = 14.3 μM and kinact = 0.018/min. Conclusions: These In Vitro results demonstrate a significant interaction between DOM and ERY. This interaction will lead to higher DOM levels which could result in altered therapeutic efficacy and toxicity in patients. This drug-drug interaction is of importance to be known to physicians caring for patients with gastroparesis.
T1271 Assessment of Drug Effects On Gastric Emptying and Contractility Using Wireless Capsule Manometry Amjad Mreyoud, Inna Rozov, John Moore, Gregory E. Wilding, Elias Khawam, Jeffrey M. Lackner, John R. Semler, Michael D. Sitrin Purpose: The SmartPill is a new capsule device containing pH, pressure, and temperature sensors that permits ambulatory assessment of transit times and motility throughout the GI tract. Previous studies have shown good correlation of gastric emptying time (GET) of the SmartPill with scintigraphy. The purpose of this study was to evaluate the ability of the SmartPill to detect effects of drugs on GET and gastric contractility in healthy subjects. The primary endpoint was the drugs' effects on GET. The secondary endpoint was the drugs' influence on gastric contraction frequency (contractions per min). Methods: 15 healthy adults (12 M, 3 F) were studied 3 times when they received in random order over 20 min: saline, erythromycin IV 150 mg, or morphine IV 0.5mg/kg/BW. Subjects ate a standard meal (SmartBar) after each infusion, and subsequently ingested the SmartPill. Data were recorded for 8 hours after SmartPill ingestion, and the results were analyzed using MotiliGi software and GIMS Data Viewer v.1.4 provided by the manufacturer. GET was defined as the time from capsule ingestion to an abrupt rise in pH as the capsule entered the duodenum. The frequency of contractions during capsule residence in the stomach was evaluated using both 10 mmHg and 20 mmHg as the minimum pressure threshold. Results: GET of the SmartPill was significantly shorter after erythromycin than either saline or morphine. GET with erythromycin was shorter than saline in 13/15 subjects and was shorter than morphine in 14/15. Morphine tended to delay emptying of the SmartPill, and was longer than saline in 11/15 subjects. Using both a 10 mmHg and 20 mmHg contraction threshold, there was trend toward a greater frequency of gastric contractions with erythromycin and a reduced frequency of gastric contractions with morphine that did not reach statistical significance. Conclusions: The SmartPill detected acceleration of gastric emptying induced by erythromycin. Gastric emptying of the SmartPill tended to be slowed by morphine, associated with a decrease in gastric contraction frequency. These results indicate that the SmartPill may be a useful tool to assess pharmacologic effects on gastric transit and contractility and aid in development of drugs to treat gastric motor disorders.
T1269 Effect of Poncirus Trifoliata On Colonic Motility in Spinal Cord Injured Rats Yong Sung Kim, Ki Hoon Kim, Suck Chei Choi, Jung Taek Oh, Yong Leol Oh, Mincheol Joo, Moon Young Lee Introduction: The fruit of Poncirus trifoliata (PT) has been used for gastrointestinal and skin disease in Eastern countries. It has been reported that PT has a prokinetic activity effect in GI tract and we have shown that PT increased spontaneous contractions selectively in distal colon of rats.1 Objectives: The purpose of this study was to investigate the effect of PT on improvement of fecal impaction and spontaneous contraction of colonic strip in spinal cord injured (SCI) rats. Methods: Fifteen adult Sprague-Dawely female rats(200~250 g) were used. A complete spinal cord transection was performed surgically at the T10 cord level. Experimental groups were assigned into 3 groups: Control (n=5), SCI+vehicle (n=5) and SCI+PT (n=5). PT extract was administered 100 mg/kg every 24 hours from 1st operation day to 7th day. We measured the body weight, amount of food intake, the number and the weight of fecal pellets every morning. After 1week of operation, whole colon was removed under anesthesia and was divided into proximal and distal segments. Each segment of colon was mounted with longitudinal direction in an organ bath. We measured spontaneous contraction and compared the area under the curve (AUC) in each segments. The change of contractility under acetylcholine (Ach, 10-6 M), 40 mM KCl solution and L-NAME (104 M) was measured. Results : The fecal number and weight were significantly higher in the group of SCI+PT than SCI+vehicle group (p<0.05). In organ bath study, spontaneous contraction of proximal segment in SCI+vehicle and SCI+PT group were significantly increased compared to control group. But spontaneous contraction of distal segment was only increased in SCI+vehicle group. Spontaneous contraction of distal segment under Ach or KCl in SCI+vehicle group was significantly decreased than other groups(p<0.05), but it was not different between SCI+PT and control group. Under L-NAME treatment, spontaneous contraction of distal segment in SCI+PT group was increased compared to other groups. Conclusion: These results suggest that PT might be useful to promote bowel emptying in spinal cord injured rats. Ref. 1. MY LEE et al. The extract of Poncirus Trifoliata increased the spontaneous contractions of colon in rat. Joint International Meeting for NGM 2008
a - erythromycin vs saline, p<0.001 b - erythromycin vs morphine, p<0.01 c - morphine vs saline, p=0.11 d - erythromycin vs morphine group, p=0.12 e - morphine vs saline group, p=0.14
AGA Abstracts
A-536
and most (83%) participants thought that the response scales from none to very severe captured their symptom experience and were simple to use. All participants reported that the diary items captured their symptom experience with gastroparesis. Participants with diabetic or idiopathic gastroparesis reported similar symptoms and had comparable comprehension of the GCSI daily diary, indicating that the set of symptom items was relevant across different gastroparesis etiologies. Conclusions: The GCSI daily diary was relevant to patients with symptoms of gastroparesis. Together with extensive previous validation of the GCSI, this GCSI daily symptom diary has the characteristics to be a good patient reported outcome for evaluating the effectiveness of treatments in clinical trials for gastroparesis.
T1270 Food Does Not Affect the Oral Bioavailability of Prucalopride Vera J. Van de Velde, Jannie Ausma, Lieve Vandeplassche Background: Prucalopride (PRU), a dihydrobenzofurancarboxamide derivate, is a 5-HT4 receptor agonist with strong enterokinetic activity. PRU is currently developed for treatment of chronic constipation in adults. The recommended therapeutic dosage is 2 mg PRU o.d.; the formulation is a direct-compression tablet containing prucalopride succinate, equivalent to 2 mg prucalopride base. Objective: The present study investigated the effect of concomitant food intake on the oral bioavailability of PRU. Methods: Following a balanced, 2-way crossover randomization, 6 male and 8 female subjects were administered a 2-mg PRU tablet in fasting conditions and immediately after a high-fat, high-calorie breakfast. The washout period between drug doses was 2 weeks. Plasma concentrations of PRU were determined up to 96 h after each dose, using a validated radioimmunoassay with a lower limit of quantification of 0.1 ng/mL. Pharmacokinetic parameters were calculated using standard non-compartmental methods. Results: Pharmacokinetic parameters (mean ± SD) are summarized in the table below. There were no statistically significant differences between fasted and fed intake for any of the pharmacokinetic parameters. Mean treatment ratios and associated 90% confidence intervals of log-transformed Cmax (98-115%), AUClast and AUC∞ (both 91-101%) were well contained in the 80-125% equivalence range. Both treatments appeared to be safe, and reasonably well tolerated. Other than headache, the most frequently reported side-effects (diarrhoea, flatulence, nausea) in this population of healthy subjects were of gastro-intestinal origin, related to PRU's pharmacodynamic profile. Their incidence was similar for both treatments. Headache occurred more frequently when subjects were dosed in the fasting state. Conclusion: Food did not have an effect on the oral bioavailability of PRU. Rate and extent of absorption were not different after dosing to fasted subjects or after a high-fat, high calorie breakfast.
T1268 Pharmacologic Interaction of Domperidone and Erythromycin: MechanismBased Enzyme Inhibition of Domperidone Hydroxylation By Erythromycin in Human Liver Microsomes Din Ung, Henry P. Parkman, Swati Nagar The prokinetic drugs domperidone (DOM) and erythromycin (ERY) are used to treat patients with gastroparesis. In refractory patients with gastroparesis, they can be used in combination. DOM and ERY are metabolized by cytochrome P450 (CYP) 3A4, an enzyme known to be inhibited by ERY. Aim: The aim of this study examines the potential drug-drug interaction of DOM and ERY in pooled human liver microsomes (HLMs). Methods: Time- and concentration-dependent enzyme assays were performed in HLM to evaluate drug-drug interaction mediated by mechanism-based inactivation. CYP activity towards DOM was characterized in HLM pre-incubated with ERY at various concentrations (10 - 200 μM) and pre-incubation times (10 - 40 min). Pre-incubation mixtures consisted of 0.5 mg/ml HLM, NADPH-regenerating system, ERY, and 0.05 M potassium phosphate buffer (pH 7.4). After pre-incubation at 37°C, DOM was added to the mixture and further incubated for 30min. Reactions were terminated by addition of cold acetonitrile containing internal standard encainide. Samples were analyzed for DOM metabolites using a validated HPLC assay. Kinetics constants of inactivation were calculated graphically. Apparent rates of inactivation were estimated from slopes of a plot of the log of enzyme activity remaining after pre-incubation with respect to pre-incubation time. A double-reciprocal plot of the rates of inactivation against inhibitor concentration was used to obtain estimates of concentration required for half-maximal inactivation, KI, and for maximum rate of inactivation, kinact, from the x- and y-intercepts, respectively. Results: Addition of domperidone to HLM In Vitro preparations, resulted in domperidone along with three major and two minor metabolites of DOM being observed. ERY significantly inhibited the metabolism of DOM. The major metabolite of interest was 5-hydroxydomperidone, which displayed Michaelis-Menten kinetics with a Vmax = 0.53 ± 0.03 nmol/min/mg protein and Km = 53 ± 10 μM; data expressed as mean ± S.E., n = 3. A time- and concentration-dependent inhibition (i.e. reduced DOM metabolism) of 5hydroxydomperidone by ERY was observed in HLM. Estimates of inactivation kinetic constants were: KI = 14.3 μM and kinact = 0.018/min. Conclusions: These In Vitro results demonstrate a significant interaction between DOM and ERY. This interaction will lead to higher DOM levels which could result in altered therapeutic efficacy and toxicity in patients. This drug-drug interaction is of importance to be known to physicians caring for patients with gastroparesis.
T1271 Assessment of Drug Effects On Gastric Emptying and Contractility Using Wireless Capsule Manometry Amjad Mreyoud, Inna Rozov, John Moore, Gregory E. Wilding, Elias Khawam, Jeffrey M. Lackner, John R. Semler, Michael D. Sitrin Purpose: The SmartPill is a new capsule device containing pH, pressure, and temperature sensors that permits ambulatory assessment of transit times and motility throughout the GI tract. Previous studies have shown good correlation of gastric emptying time (GET) of the SmartPill with scintigraphy. The purpose of this study was to evaluate the ability of the SmartPill to detect effects of drugs on GET and gastric contractility in healthy subjects. The primary endpoint was the drugs' effects on GET. The secondary endpoint was the drugs' influence on gastric contraction frequency (contractions per min). Methods: 15 healthy adults (12 M, 3 F) were studied 3 times when they received in random order over 20 min: saline, erythromycin IV 150 mg, or morphine IV 0.5mg/kg/BW. Subjects ate a standard meal (SmartBar) after each infusion, and subsequently ingested the SmartPill. Data were recorded for 8 hours after SmartPill ingestion, and the results were analyzed using MotiliGi software and GIMS Data Viewer v.1.4 provided by the manufacturer. GET was defined as the time from capsule ingestion to an abrupt rise in pH as the capsule entered the duodenum. The frequency of contractions during capsule residence in the stomach was evaluated using both 10 mmHg and 20 mmHg as the minimum pressure threshold. Results: GET of the SmartPill was significantly shorter after erythromycin than either saline or morphine. GET with erythromycin was shorter than saline in 13/15 subjects and was shorter than morphine in 14/15. Morphine tended to delay emptying of the SmartPill, and was longer than saline in 11/15 subjects. Using both a 10 mmHg and 20 mmHg contraction threshold, there was trend toward a greater frequency of gastric contractions with erythromycin and a reduced frequency of gastric contractions with morphine that did not reach statistical significance. Conclusions: The SmartPill detected acceleration of gastric emptying induced by erythromycin. Gastric emptying of the SmartPill tended to be slowed by morphine, associated with a decrease in gastric contraction frequency. These results indicate that the SmartPill may be a useful tool to assess pharmacologic effects on gastric transit and contractility and aid in development of drugs to treat gastric motor disorders.
T1269 Effect of Poncirus Trifoliata On Colonic Motility in Spinal Cord Injured Rats Yong Sung Kim, Ki Hoon Kim, Suck Chei Choi, Jung Taek Oh, Yong Leol Oh, Mincheol Joo, Moon Young Lee Introduction: The fruit of Poncirus trifoliata (PT) has been used for gastrointestinal and skin disease in Eastern countries. It has been reported that PT has a prokinetic activity effect in GI tract and we have shown that PT increased spontaneous contractions selectively in distal colon of rats.1 Objectives: The purpose of this study was to investigate the effect of PT on improvement of fecal impaction and spontaneous contraction of colonic strip in spinal cord injured (SCI) rats. Methods: Fifteen adult Sprague-Dawely female rats(200~250 g) were used. A complete spinal cord transection was performed surgically at the T10 cord level. Experimental groups were assigned into 3 groups: Control (n=5), SCI+vehicle (n=5) and SCI+PT (n=5). PT extract was administered 100 mg/kg every 24 hours from 1st operation day to 7th day. We measured the body weight, amount of food intake, the number and the weight of fecal pellets every morning. After 1week of operation, whole colon was removed under anesthesia and was divided into proximal and distal segments. Each segment of colon was mounted with longitudinal direction in an organ bath. We measured spontaneous contraction and compared the area under the curve (AUC) in each segments. The change of contractility under acetylcholine (Ach, 10-6 M), 40 mM KCl solution and L-NAME (104 M) was measured. Results : The fecal number and weight were significantly higher in the group of SCI+PT than SCI+vehicle group (p<0.05). In organ bath study, spontaneous contraction of proximal segment in SCI+vehicle and SCI+PT group were significantly increased compared to control group. But spontaneous contraction of distal segment was only increased in SCI+vehicle group. Spontaneous contraction of distal segment under Ach or KCl in SCI+vehicle group was significantly decreased than other groups(p<0.05), but it was not different between SCI+PT and control group. Under L-NAME treatment, spontaneous contraction of distal segment in SCI+PT group was increased compared to other groups. Conclusion: These results suggest that PT might be useful to promote bowel emptying in spinal cord injured rats. Ref. 1. MY LEE et al. The extract of Poncirus Trifoliata increased the spontaneous contractions of colon in rat. Joint International Meeting for NGM 2008
a - erythromycin vs saline, p<0.001 b - erythromycin vs morphine, p<0.01 c - morphine vs saline, p=0.11 d - erythromycin vs morphine group, p=0.12 e - morphine vs saline group, p=0.14
AGA Abstracts
A-536