ABSTRACT:The absorption, metabolism, and excretion of the oral direct thrombin inhibitor, ximelagatran, and its active form, melagatran, were separately investigated in rats, dogs, and healthy male human subjects after administration of oral and intravenous (i.v.) single doses. Ximelagatran was rapidly absorbed and metabolized following oral administration, with melagatran as the predominant compound in plasma. Two intermediates (ethyl-melagatran and OH-melagatran) that were subsequently metabolized to melagatran were also identified in plasma and were rapidly eliminated. Melagatran given i.v. had relatively low plasma clearance, small volume of distribution, and short elimination half-life. The oral absorption of melagatran was low and highly variable. It was primarily renally cleared, and the renal clearance agreed well with the glomerular filtration rate. Ximelagatran was extensively metabolized, and only trace amounts were renally excreted. Melagatran was the major compound in urine and feces after administration of ximelagatran. Appreciable quantities of ethyl-melagatran were also recovered in rat, dog, and human feces after oral administration, suggesting reduction of the hydroxyamidine group of ximelagatran in the gastrointestinal tract, as demonstrated when ximelagatran was incubated with feces homogenate. Polar metabolites in urine and feces (all species) accounted for a relatively small fraction of the dose. The bioavailability of melagatran following oral administration of ximelagatran was 5 to 10% in rats, 10 to 50% in dogs, and about 20% in humans, with low between-subject variation. The fraction of ximelagatran absorbed was at least 40 to 70% in all species. First-pass metabolism of ximelagatran with subsequent biliary excretion of the formed metabolites account for the lower bioavailability of melagatran.
SUMMARYThe CYP4A enzymes catalyze the formation of 20-hydroxyeicosatetraenoic acid (20-HETE), which has potent effects on the renal vasculature and tubular ion transport. Based on an increased 20-HETE formation in renal microsomes from spontaneously hypertensive rats, it has been proposed that increased expression of the CYP4A genes is an early event in the development of hypertension in these animals. To test this hypothesis, we developed RNase protection assays for specific detection of the individual CYP4A genes in the kidneys of spontaneously hypertensive and Wistar-Kyoto rats. Distinct age-dependent patterns of expression were observed for the individual CYP4A genes, with only CYP4A3 mRNA measurable in the kidneys of 1-week-old rats. CYP4A1 and CYP4A8 mRNA were detectable by 3 weeks of age and CYP4A2 mRNA at 5 weeks of age. The expression of CYP4A1 and CYP4A3 varied 4 -5-fold throughout development and was highest between 3 and 5 weeks of age, declining steadily thereafter to 20% of their maximal level by 9 weeks of age. CYP4A2 mRNA levels increased steadily between 5 and 9 weeks of age, whereas CYP4A8 mRNA levels were relatively constant throughout development. The CYP4A3 mRNA level was significantly increased 1.6 -2-fold in the cortex and outer medulla of 1-4-week-old spontaneously hypertensive rat kidneys relative to the corresponding level in the Wistar-Kyoto. A similar 1.4 -1.7-fold increase in CYP4A8 mRNA was also found in 3-and 4-weekold spontaneously hypertensive kidneys. Accompanying the increased expression of CYP4A3 and CYP4A8 mRNA in the prehypertensive rats were corresponding changes in functional CYP4A measured as either arachidonic acid or lauric acid -hydroxylase activity (1.4 -2.0-fold increases) and CYP4A protein levels. After 4 weeks of age, the level of CYP4A mRNA, enzyme activity, and protein were similar in the kidneys of Wistar-Kyoto and spontaneously hypertensive rats. The findings suggest that the expression of CYP4A3 and CYP4A8 may be critical to the early changes in eicosanoid formation and renal function in the young spontaneously hypertensive rat.
This multicenter, observational drug utilization (DU) study (NCT01594996) investigated the profile of patients and specialist providers who prescribed extended release quetiapine fumarate (quetiapine XR) for treatment of major depressive disorder (MDD) across five European countries (Germany, Italy, Romania, Spain, and Sweden). A DU data abstraction form captured information on the characteristics of physicians, patients, and drugs utilized in the medical management of depressive episodes in MDD, where the therapeutic regimen included quetiapine XR. Data were reported descriptively. This analysis included 811 patients. Psychiatric histories indicated a burden of severe MDD in these patients. Patient demographics were similar across countries; however, those in Sweden had a younger mean age. Physicians’ ratings of the therapeutic effect of prior treatment with antidepressants suggested the need for an add-on treatment for most patients. Overall, 15.7% of patients initiated quetiapine XR treatment as monotherapy. Presence of psychotic symptoms during depressive episodes predicted treatment with higher than recommended doses of quetiapine XR (odds ratio=3.11; 95% confidence interval: 1.6–6.0). This analysis demonstrated similarities in DU across the countries analyzed, largely in accordance with the recommended dose of quetiapine XR as an adjunctive therapy to antidepressants in MDD (50–300 mg/day).
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.