Metabolism, excretion, and pharmacokinetics of [14c]-radiolabeled aleglitazar: a phase I, nonrandomized, open-label, single-center, single-dose study in healthy male volunteers.

BACKGROUND: Aleglitazar is a dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist with a balanced activity (similar half-maximal effective concentrations) toward PPAR-α and -γ that is in clinical development for the treatment of patients who have experienced an acute coronary syndrome and have type 2 diabetes mellitus. OBJECTIVE: This study aimed to characterize the metabolic profile and the routes and rates of elimination of aleglitazar and its major metabolites in humans. METHODS: In this Phase I, nonrandomized, open-label, single-center, single-dose study, 6 healthy male subjects each received a single oral dose of 300 µg [(14)C]-labeled aleglitazar. Total urine and feces were collected for up to 15 days. Venous blood samples were collected to determine the plasma concentrations of aleglitazar and its metabolites and for radioactivity counting. RESULTS: The median age (range) and mean (SD) body mass index of subjects were 48 (41-60) years and 24.8 (3.0) kg/m(2), respectively. Recovery of total radioactivity, as a percentage of the dose administered, was high (93 [3]%). Aleglitazar was predominantly eliminated in feces (mean, 66% [range, 55%-74%]), with only 28% (range, 22%-36%) of the radioactivity recovered in urine. Only a mean (SD) of 1.8 (0.8)% of aleglitazar was eliminated unchanged as parent compound in feces and only 0.3 (0.4)% was eliminated in urine. Almost all excreted drug-related material could be attributed to its 2 main metabolites, M1 (21%) and M6 (38%). Treatment with aleglitazar was well tolerated, and no serious adverse events were reported. CONCLUSIONS: In healthy volunteers, aleglitazar was excreted mainly in the form of inactive metabolites, mostly M1 and M6, with only a small proportion eliminated unchanged.

Pharmacokinetics and metabolism of the dipeptidyl peptidase IV inhibitor carmegliptin in rats, dogs, and monkeys.

The pharmacokinetics and excretion of carmegliptin, a novel dipeptidyl peptidase IV inhibitor, were examined in rats, dogs, and cynomolgus monkeys. Carmegliptin exhibited a moderate clearance, extensive tissue distribution, and a variable oral bioavailability of 28-174%. Due to saturation of intestinal active secretion, the area under the plasma concentration-time curve (AUC) in dogs and monkeys increased in a more than dose-proportional manner over an oral dose range of 2.5-10 mg/kg. Following oral administration of [(14)C]carmegliptin at 3 mg/kg, > 94% of the radioactive dose was recovered in 72-h post-dose from Wistar rats and Beagle dogs. Virtually, the entire administered radioactive dose was excreted unchanged in urine, intestinal lumen, and bile. Approximately 36%, 29%, and 19% of the dose were excreted by respective routes. Consistently, in vitro, carmegliptin was highly resistant to hepatic metabolism in all species tested. Based on in vitro studies, carmegliptin is a good substrate for Mdr1/MDR1. Breast cancer resistance protein (Bcrp) is not expected to be involved in the transport of carmegliptin since in vitro carmegliptin was not significantly transported by this transporter. The very high extravascular distribution of carmegliptin in the intestinal tissues, as demonstrated in Wistar rats and Beagle dogs, could play a significant role in its therapeutic effect.

Glutathione conjugates of 4-hydroxy-2(E)-nonenal as biomarkers of hepatic oxidative stress-induced lipid peroxidation in rats.

Here we present a simple, specific, and sensitive liquid chromatography/mass spectrometry method to measure 4-hydroxy-2(E)-nonenal-glutathione (HNE-GSH), the major stable hepatic metabolite of HNE after GSH conjugation, as a marker of oxidative stress in rat liver and hepatocytes. Commonly employed methods for the measurement of lipid peroxidation-derived free aldehydes or modified proteins suffer from the artificial formation of HNE or HNE adducts to cellular molecules during sample preparation and derivatization, resulting in an overestimation of background levels. Basal levels of HNE-GSH in liver tissue from untreated rats were detected in amounts of 20 pmol/g liver. Rats exposed to a single dose of iron nitrilotriacetate (Fe(III)NTA; 15 mg Fe/kg bw, ip), a model compound for the induction of oxidative stress, revealed a fivefold increase in the hepatic HNE-GSH levels compared to controls 5 h after dosing. Moreover, a significant increase in HNE-mercapturic acid (HNE-MA) and its reduced metabolite DHN-MA was evident at 5 or 24 h after treatment, which was also reflected in increased plasma concentrations of these secondary HNE-GSH metabolites. In agreement with the in vivo data, a time-dependent increase in the levels of HNE-GSH from <1 to 123 +/- 16 pmol/10(6) cells over 5 h was detected in rat hepatocytes treated with Fe(III)NTA (150 microM). An increase in cellular HNE-GSH from <1.0 to 7.2 +/- 0.3 pmol/10(6) cells could be observed in rat hepatocytes treated with allyl alcohol (500 microM, 3 h), known for generation of HNE in hepatocytes. These data suggest that the direct measurement of the stable GSH conjugation product of cellular HNE in rat primary hepatocytes or its secondary metabolites may represent a reliable biomarker of oxidative stress-induced lipid peroxidation in rat liver in vivo.