Systemic bile acid sensing by G protein-coupled bile acid receptor 1 (GPBAR1) promotes PYY and GLP-1 release.

BACKGROUND AND PURPOSE: Nutrient sensing in the gut is believed to be accomplished through activation of GPCRs expressed on enteroendocrine cells. In particular, L-cells located predominantly in distal regions of the gut secrete glucagon-like peptide 1 (GLP-1) and peptide tyrosine-tyrosine (PYY) upon stimulation by nutrients and bile acids (BA). The study was designed to address the mechanism of hormone secretion in L-cells stimulated by the BA receptor G protein-coupled bile acid receptor 1 (GPBAR1). EXPERIMENTAL APPROACH: A novel, selective, orally bioavailable, and potent GPBAR1 agonist, RO5527239, was synthesized in order to investigate L-cell secretion in vitro and in vivo in mice and monkey. In analogy to BA, RO5527239 was conjugated with taurine to reduce p.o. bioavailability yet retaining its potency. Using RO5527239 and tauro-RO5527239, the acute secretion effects on L-cells were addressed via different routes of administration. KEY RESULTS: GPBAR1 signalling triggers the co-secretion of PYY and GLP-1, and leads to improved glucose tolerance. The strong correlation of plasma drug exposure and plasma PYY levels suggests activation of GPBAR1 from systemically accessible compartments. In contrast to the orally bioavailable agonist RO5527239, we show that tauro-RO5527239 triggers PYY release only when applied intravenously. Compared to mice, a slower and more sustained PYY secretion was observed in monkeys. CONCLUSION AND IMPLICATIONS: Selective GPBAR1 activation elicits a strong secretagogue effect on L-cells, which primarily requires systemic exposure. We suggest that GPBAR1 is a key player in the intestinal proximal-distal loop that mediates the early phase of nutrient-evoked L-cell secretion effects.

Effect of iontophoresis and penetration enhancers on transdermal absorption of metopimazine.

BACKGROUND: Metopimazine is an antiemetic drug already used by oral and rectal administration. It would be interesting to develop a new formulation for a transdermal administration. OBJECTIVE: The objective of this study was to determine the influence of iontophoresis on the metopimazine transdermal absorption and the possible synergistic enhancement with chemical enhancers. METHODS: Transdermal transport of metopimazine was studied in vitro in a Franz cell with pig skin according to the following protocol: 1h of iontophoresis followed by 7h of passive diffusion. Different current densities were applied: 0, 0.125, 0.25 and 0.5 mA/cm(2). Chemical enhancers used as solvent dilution were ethanol, propylene glycol and isopropyl myristate. Metopimazine was assayed by HPLC. Fourier transform infrared spectroscopy was used to determinate the interaction between chemical enhancers and stratum corneum. RESULTS: The iontophoresis has increased the percutaneous absorption of metopimazine and has decreased the lag time with 3.85+/-0.90 microg/(cm(2)h) and 1.9h for 0.5 mA/cm(2) and with 0.27+/-0.20 microg/(cm(2)h) and >8h for passive diffusion. Transdermal transport has been increased with current density and with isopropyl myristate and was not modified by ethanol or propylene glycol. CONCLUSION: Results indicated that iontophoresis is an effective method for transdermal administration of metopimazine.

Percutaneous absorption of metopimazine and effect of cyclodextrins.

Metopimazine (MPZ) is used to prevent emesis during chemotherapies. A transdermal delivery system of MPZ may present a great advantage in patients to improve compliance. Hydroxypropyl beta cyclodextrin (HPbetaCD) and partially methylated beta cyclodextrin (PMbetaCD) were tested to enhance the percutaneous absorption of MPZ through pig skin using Franz's cells. The MPZ hydrochloride flux was low with 0.176 +/- 0.054 microg/h/cm(2) and no flux was detected with a suspension of MPZ (base). The used characterization analyses demonstrated the formation of an inclusion complex with cyclodextrin and this complex improved percutaneous absorption of MPZ. Flux was increased to 0.240 +/- 0.032 microg/h/cm(2) and 0.566 +/- 0.057 mug/h/cm(2) for HPbetaCD and PMbetaCD, respectively, with a concentration of 20%. This study has shown that HPbetaCD and PMbetaCD improved the percutaneous penetration of MPZ. Cyclodextrin complexes increased MPZ bioavailability at the skin surface and PMbetaCD was also able to extract cutaneous fatty acids.

Evidence of lowest brain penetration of an antiemetic drug, metopimazine, compared to domperidone, metoclopramide and chlorpromazine, using an in vitro model of the blood-brain barrier.

PURPOSE: The objective of the current study was to determine the ability of some antiemetic compounds to cross the blood-brain barrier (BBB) and thereby to determine possible side effects of compounds for the central nervous system (CNS). METHODS: We compared the brain penetration of some antiemetic compounds using an in vitro BBB model consisting in brain capillary endothelial cells co-cultured with primary rat glial cells. RESULTS: This study clearly demonstrated that the metopimazine metabolite, metopimazine acid, has a very low brain penetration, lower than metopimazine and even less than the other antiemetic compounds tested in this study. CONCLUSIONS: The poor brain penetration of metopimazine acid, metopimazine biodisponible form, seems very likely related to the clinically observed difference in therapeutic and safety profile.

Randomized trial of AT-1015 for treatment of intermittent claudication. A novel 5-hydroxytryptamine antagonist with no evidence of efficacy.

AT-1015 is a novel selective 5-HT2A serotonin receptor antagonist that is known to impair platelet aggregation and vasoconstriction. Serotonin has been hypothesized to contribute to claudication symptoms in individuals with peripheral arterial disease (PAD) via microvascular vasoconstrictor and thrombotic effects. AT-1015 was thus evaluated in 439 patients with claudication who were randomized in a double-blind, placebo-controlled trial comparing 10 mg, 20 mg, and 40 mg BID versus placebo for 24 weeks. Treadmill walking performance was assessed by peak walking time (PWT) and pain-free walking time (PFWT). Quality of life (QoL) was measured by the Walking Impairment Questionnaire (WIQ) and the Health Status Survey SF-36. Limb hemodynamics was assessed with the ankle-brachial index (ABI). The 40 mg arm was terminated prematurely by recommendation of the Data Safety Monitoring Committee due to an excess number of non-fatal myocardial infarctions. At study conclusion, there were no statistically significant differences in the mean change of PWT, PFWT, ABI and QoL between the 10 mg and 20 mg BID treatment groups compared with placebo. The proportion of patients who experienced an adverse event (AE) was similar across all treatment groups. Antimuscarinic and gastrointestinal AEs were more common in the AT-1015 treatment groups. Two deaths occurred: one in the placebo group and the other in the AT-1015 20 mg group. Although a prolongation of the QTc interval was observed in all groups, this was not clinically significant (QTc > 500 ms). Mean supine pulse rates were significantly increased in all AT-1015 treatment groups, consistent with predicted antimuscarinic effects. Population pharmacokinetic analysis fit a one-compartment model with first-order absorption and elimination. These data indicate that selective serotonin receptor blockade does not improve exercise tolerance or quality of life in individuals with claudication.

Design, synthesis and anticonvulsive activities of potential prodrugs linked by two-carbon chain.

For the development of new anticonvulsive agents, GABAmimetics such as nipecotic acid, isonipecotic acid, gamma-aminobutyric acid (GABA), gamma-vinyl GABA (vigabatrin) and valproic acid were covalently coupled through an ester bond by a two-carbon linker chain as potential pro-drugs and evaluated for their anticonvulsive activities.

AT-1015, a newly synthesized 5-HT2 receptor antagonist, dissociates slowly from the 5-HT2 receptor sites in rabbit cerebral cortex membrane.

The purpose of this study was to investigate the association and dissociation kinetics of [3H]AT-1015 from 5-HT2 receptors in rabbit cerebral cortex membranes using a radioligand binding assay method and to make a comparison with those of [3H]ketanserin binding. Scatchard analysis of [3H]AT-1015 binding in rabbit cerebral cortex membranes indicated the existence of a single class of binding sites (dissociation constant, Kd = 2.18 nM). The specific binding of [3H]AT-1015 increased slowly with time and the association rate constant of [3H]AT-1015 binding (k1 = 0.1229 min-1 nM-1) was two times slower than that of [3H]ketanserin binding (k1 = 0.2451 min-1 nM-1). The dissociation rate constant of [3H]AT-1015 binding (t 1/2 = 37.03 min) was six times slower than that of [3H]ketanserin binding (t 1/2 = 6.29 min), when the addition of excess unlabelled ligands were AT-1015 and ketanserin, respectively. The dissociation rate constant of [3H]AT-1015 was slowed to a greater degree (t 1/2 = 163.40 min and t 1/2 = 198.12 min) by the addition of ketanserin and sarpogrelate as excess unlabelled ligands than was that of [3H]ketanserin (t 1/2 = 17.76 min and t 1/2 = 18.45 min) by the addition of AT-1015 and sarpogrelate as an excess unlabelled ligand, respectively. These findings on the dissociation kinetics of [3H]AT-1015 have confirmed and supported previously reported evidence of the slower dissociation of AT-1015 from 5-HT2 receptors.

Dose-finding study of oral metopimazine.

A few studies indicate a dose-response effect of the antiemetic metopimazine. The aim of this study was therefore to investigate the tolerability of increasing doses of metopimazine given orally every 4 h for eleven doses. The dose levels 20 mg, 30 mg, 40 mg, 50 mg and 60 mg were studied in 36 patients completing 46 cycles of chemotherapy. Serum concentrations of metopimazine and the acid metabolite AMPZ were measured by HPLC in 13 patients (15 cycles). The dose-limiting toxicity was moderate to severe dizziness caused by orthostatic hypotension as seen in 0, 0, 17%, 42% and 50% of patients at the respective dose levels. Other side effects were few and mild, and only a single possible extrapyramidal adverse event was observed in a patient at the 60-mg dose. High serum concentrations were not predictive for toxicity, as found on comparison of patients with and without symptoms, but in individual patients symptoms were seen at the time of Cmax. We found that metopimazine was safe with a dosage of 30 mg x 6. This dose is four times higher than that previously recommended for antiemetic use.

Bioavailability of the antiemetic metopimazine given as a microenema.

The absorption of the antiemetic metopimazine (MPZ) given as a single dose of (a) 40 mg microenema, (b) 40 mg orally and (c) 10 mg as a 60 min i.v. continuous infusion was investigated in six healthy volunteers. Blood samples were drawn and the serum concentrations of MPZ and its acid metabolite were measured. The bioavailability of MPZ given orally and as enemas was 22.3 and 19.5% respectively. Partial avoidance of hepatic first pass metabolism was seen with the enemas, which in contrast to suppositories, seems to represent a reliable form of rectal administration.

Kinetics of idaverine in healthy male subjects after single dose oral and intravenous administration.

The kinetics of idaverine was studied in an open, cross-over, partially randomized design after single oral (2 mg) and intravenous (1 and 2 mg doses to 12 healthy male subjects. In the first session, the volunteers were administered 1 mg idaverine by constant intravenous infusion during 45 min. The treatments in the second and third sessions were given according to a cross-over design, randomized in blocks of six for each session (2 mg either orally or by intravenous infusion during 45 min). The washout period between the sessions was at least 1 week. Plasma, urine and faeces were analysed for idaverine and its pharmacologically active metabolite N-desmethylidaverine by gas chromatography with nitrogen flame ionisation detection. After intravenous administration, the MRT was on average 2 hours and the mean CLS was about 900 ml.min-1. CLR is about twice the glomerular filtration rate, suggesting net tubular secretion of idaverine. The AUC and the cumulative urinary and faecal excretion values gave no indication of dose-disproportionality within the range of 1 and 2 mg administered intravenously. Maximum plasma levels of 1-3 ng.ml-1 were reached between 0.5 hours and 3 hours after oral dosing. The MRT was 4.4 hours. Systemic availability was about 29%. N-desmethylidaverine was barely detectable in plasma after all doses. Idaverine was well tolerated, only a small increase in heart rate was observed.