Stereoselective glucuronidation of carvedilol in human liver and intestinal microsomes.

BACKGROUND AND PURPOSE: Carvedilol is used clinically as a ß-adrenoceptor antagonist for the treatment of chronic heart failure and is primarily metabolized into glucuronides by UDP-glucuronosyltransferase (UGT). In this study, the stereoselective glucuronidation of carvedilol by the human liver and intestinal microsomes was examined using racemate and enantiomers. METHODS: Carvedilol glucuronidation activities at substrate concentrations of 1-1,000 µmol/l in human liver and intestinal microsomes were determined by high-performance liquid chromatography with fluorescence detection, and the kinetic parameters were estimated. RESULTS: The activities of S-glucuronidation toward racemic and enantiomeric carvedilol in liver microsomes were higher than those of R-glucuronidation at all substrate concentrations examined. In intestinal microsomes, the activities of S-glucuronidation from racemic and enantiomeric carvedilol at ≤100 µmol/l substrates were higher than those of R-glucuronidation, whereas the glucuronidation activities at ≥200 µmol/l substrates exhibited the opposite stereoselectivity (R > S) compared with those at ≤100 µmol/l substrates. The activities of R- and S-calvedilol glucuronidation from racemate and enantiomers in the liver and intestinal microsomes were decreased at substrate concentrations of ≥100 or 200 µmol/l, and the kinetics at substrate concentrations of 1-100 and 1-1,000 µmol/l fitted with Michaelis-Menten and substrate inhibition models, respectively. The stereoselectivities of CL(int) values for carvedilol glucuronidation followed by Michaelis-Menten and substrate inhibition models were R < S for liver microsomes and R ≈ S for intestinal microsomes. CONCLUSION: These findings demonstrate that the stereoselectivity of carvedilol glucuronidation was different between human liver and intestinal microsomes, and suggest that the difference is due to the tissue-specific expression of UGT isoforms involved in the glucuronidation of carvedilol.

[Prophylactic effect of tropisetron hydrochloride against nausea and vomiting in patients receiving chemotherapy for hematological malignancies].

To establish the effectiveness of oral 5-HT(3) antagonist, oral 5 mg tropisetron was introduced in the 21 cases with hematological malignancies for the prevention of chemotherapy-induced nausea and vomiting. Nausea and vomiting did not develop in 81% of patients receiving the tropisetron in this study. The results suggested that oral tropisetron is effective for the control of acute, and to a lesser extent, delayed, nausea and vomiting. The drug enhanced patients' quality of life and reduced the clinical cost. In conclusion, tropisetron is effective for the prevention of chemotherapy-induced nausea and vomiting in treatment for hematological malignancies. It is suitable as first-line therapy for outpatients.

Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis.

RATIONALE: Pulmonary alveolar microlithiasis is an autosomal recessive disorder in which microliths are formed in the alveolar space. OBJECTIVES: To identify the responsible gene that causes pulmonary alveolar microlithiasis. METHODS: By means of a genomewide single-nucleotide polymorphism analysis using DNA from three patients, we have narrowed the region in which the candidate gene is located. From this region, we have identified a gene that has mutations in all patients with pulmonary alveolar microlithiasis. MEASUREMENTS AND MAIN RESULTS: We identified a candidate gene, SLC34A2, that encodes a type IIb sodium phosphate cotransporter and that is mutated in six of six patients investigated. SLC34A2 is specifically expressed in type II alveolar cells, and the mutations abolished the normal gene function. CONCLUSION: Mutations in the SLC34A2 gene that abolish normal gene function cause pulmonary alveolar microlithiasis.

Effects of pressure exerted on the skin by elastic cord on the core temperature, body weight loss and salivary secretion rate at 35 degrees C.

Effects of pressure exerted on the skin by elastic cord on the core temperature, body weight loss and salivary secretion rate were studied under conditions of ambient temperature of 35 degrees C and a relative humidity of 60%. Twelve healthy females, aged 18-23 years, served as subjects. The subjects entered a bioclimatic chamber and rested quietly in a chair for 80 min. Then, skin pressure was exerted by applying elastic cord (8.5 mm wide) to six different skin areas, such as axilla, under-bust, waist, inguines, thighs and ankles. The values of skin pressure by elastic cord ranged from 11.9 to 33.3 g/cm(2). In the control experiment, wrapping with an elastic cord was loosely performed without any skin pressure. Rectal and skin temperatures, body weight loss by sweating and salivary secretion rate were measured throughout the 160 min experimental period. Core temperature increased more significantly under pressure exerted on the skin. Body weight loss by mainly sweating and salivary secretion rate were significantly suppressed under pressure exerted on the skin. We discussed the physiological mechanisms in terms of suppression of central nervous activity as to why significant increase of core temperatures, inhibition of body weight loss mainly by sweating and of salivary secretion rate occurred, and furthermore practical significance of these findings for impairment of digestion, swallowing, vocalizing, defense against disease bacteria and sport activity.