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Steroid metabolism in the cat. Biliary and urinary excretion of metabolites of [4-14C] oestradiol.

ABSTRACT: 1. [4-(14)C]Oestradiol was administered to seven male, seven female and two castrated male cats as a single intravenous injection. Bile and urine were collected for 6h. 2. The radioactivity was excreted mainly in the bile of all animals (53-60%); only approx. 1% of the dose appeared in the urine. 3. Bile and urine samples were hydrolysed successively by beta-glucuronidase, cold acid and hot acid. There were significant differences (P<0.005) between the percentage of the dose present in the bile fractions hydrolysed by beta-glucuronidase (male, 9.0+/-1.7%; female, 18.6+/-1.45%) and by cold acid (male, 18.9+/-1.44%; female 12.1+/-1.02%). The excretion of radioactivity in these fractions by the castrated male cats was closer to that of female cats. 4. Approx. 20-27% of the dose could not be extracted from aqueous solution (pH10.5) by ethyl acetate-ether after hydrolysis.

SUBMITTER: Karim MF

PROVIDER: S-EPMC1178859 | biostudies-other | 1970 Apr

REPOSITORIES: biostudies-other

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Project description:Background and objectiveDifelikefalin, a selective kappa-opioid receptor agonist, is the first approved treatment for moderate-to-severe pruritus in patients with end-stage renal disease (ESRD) on hemodialysis (HD) in the USA and Europe. The purpose of this open-label study was to investigate the pharmacokinetics and disposition of [14C]difelikefalin following a single intravenous dose in subjects with normal renal function and subjects on HD.MethodsTwelve adult males (n = 6 healthy subjects; n = 6 subjects on HD) received single intravenous doses of [14C]difelikefalin containing 100 µCi (total doses of 1.7-3.0 μg/kg difelikefalin). Blood, urine, feces, and dialysate samples (when applicable) were collected after dosing.ResultsThe median time to maximum concentration was similar for HD and healthy subjects, occurring at 5 min post-dose. The mean area under the concentration-time curve (AUC) was approximately 11-fold higher in HD versus healthy subjects; mean plasma half-life was 38.0 h and 2.6 h, respectively. In healthy subjects, 80.5% of the dose was recovered in urine, and 11.3% was recovered in feces. In subjects on HD, 58.8% of the dose was recovered in feces, and 19.5% was recovered in dialysate [for subjects on HD with residual kidney function (n = 3), 11.2% was recovered in urine]. Based on plasma AUClast, parent [14C]difelikefalin was the most abundant analyte in systemic circulation (> 99% of total exposure) for both cohorts. Metabolite profiles in urine and feces suggested minimal metabolism of the parent compound.ConclusionIn subjects on HD, difelikefalin total exposure was higher and plasma half-life was longer compared with subjects with intact renal function. Metabolism was low in both healthy subjects and subjects on HD, with unchanged drug representing > 99% of systemic circulation; however, the route of excretion was primarily into urine versus feces in healthy subjects, and feces versus dialysate in subjects on HD.RegistrationClinicalTrials.gov NCT03947970.

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Steroid metabolism in the cat. Biliary and urinary excretion of metabolites of [4-14C] oestradiol.

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