Role of clock genes in gastrointestinal motility

Biological rhythms coordinate the timing of our internal bodily functions. Colonic motility follows a rhythm as well: most people will have a bowel movement in the morning and rarely during the night. Recent work provides a potential mechanism for this observation: the mouse colon possesses a functional circadian clock as well as a subset of rhythmically expressed genes that may directly impact on colonic motility. Furthermore, measures of colonic motility such as the colonic tissue contractile response to acetylcholine, stool output, and intracolonic pressure changes vary as a function of the time of day, but these variations are attenuated in mice with disrupted clock function. These laboratory findings are supported by clinical observations. Gastrointestinal symptoms such as diarrhea or constipation are prevalent among shift workers and time-zone travelers, both of which are conditions associated with disruptions in biological rhythms. This review will discuss new insights into the role of clock genes in colonic motility and their potential clinical relevance

Population pharmacokinetics of S(−)-carvedilol in healthy volunteers after administration of the immediate-release (IR) and the new controlled-release (CR) dosage forms of the racemate

Carvedilol is a β1-, β1-, and α1-adrenoreceptor blocker indicated for treatment of hypertension and mild-tosevere congestive heart failure. The objective of this study was to develop and evaluate a single population model that describesS(−)-carvedilol pharmacokinetics from both the immediate-release (IR) and the new controlled-release dosage forms of the racemate. Carvedilol IR data (1270 measurements) were obtained from 2 open-label studies (50 mg/25 mg Q12 hours for 2 doses). Carvedilol CR data (2058 measurements) were obtained from an open-label, nonrandomized, dose-rising (10, 20, 40, and 80 mg), 4-period balanced crossover study. All data were simultaneously analyzed using NONMEM V. Leverage analysis and internal evaluations were conducted for the final model. A 2-compartment model with first-order absorption and elimination provided the best fit. The model included different absorption rates (KAs) for the CR and IR morning (IRAM) and evening (IRPM) doses; incorporating change-points at certain times. Estimates of KAs indicated that the absorption was slower at equivalent times and extended for CR relative to IR carvedilol. Oral clearance ofS(−)-carvedilol was 149 L/h. The IRPM and the CR doses had bioavailability (Frel) of 0.80 and 0.76, respectively, relative to the IRAM dose. The inter-subject variability in KAs was lower for the CR dosage form than the original IR dosage form. Estimation of interoccasion variability on KAs and Frel for the CR dosage form improved the fit. The model performed well in simulation and leverage analysis indicated its robustness. The model will be a useful tool for future simulation studies