Pharmacokinetics, hydrolysis and aromatisation of norethisterone-3-oxime in female cynomolgus monkey

Abstract

Norethisterone-3-oxime (NETO) was administered to 3 female cynomolgus monkeys intragastrically and, after a wash-out period of 2-5 weeks, intravenously at a dose of 1 mg/kg. The radioactive dose of tritiated NETO was 20 microCi/kg for both treatments. For i.v. injection, a 30% propylene glycol/water solution and for i.g. administration an aqueous microcrystalline suspension was used. Excretion of radiolabel in urine and feces was followed for 5 days and plasma samples were obtained up to 2 days after administrations. In all samples (urine, feces and plasma) radioactivity was determined. Extracts from plasma samples were subjected to HPLC separation of drug and metabolites, as well as NETO and NET (metabolite of NETO after hydrolysis of the oxime group) levels were determined. In addition, EE2 (ethinylestradiol, A-ring aromatised metabolite of NET) levels were estimated using a specifically designed HPLC system for separation. Quantification of EE2 was achieved by radioimmunoassay (RIA) of specific eluate fractions. The results demonstrate that [3H]-NETO was absorbed completely at a dose level of 1 mg/kg, and excreted predominantly via the kidneys. A urinary to fecal excretion ratio of 1.5 (i.v.) or 1.0 (i.g.) was found. Renal excretion of total radiolabel proceeded with a half-life of about 0.8 (i.v.) or 1.1 (i.g.) days. Balances were incomplete, probably due to technical reasons. Orally administered NETO was highly bioavailable (84.0 +/- 16.9% of dose) but rapidly cleared from plasma (total clearance corresponded to 97% of plasma liver flow). The clearance from plasma is equivalent to the metabolic clearance because almost no unchanged NETO is excreted. Extensive metabolism of the parent drug was observed leading to at least two pharmacologically active metabolites (NET, EE2). The main progestogenic metabolite was NET reaching similar high plasma levels as NETO. EE2 turned out to be a metabolite of NETO and a conversion rate of below 0.5% of dose was estimated. However, due to its high estrogenic potency EE2 might contribute to the overall pharmacological pattern of NETO in the cynomolgus monkey.

The Pharmacokinetics and Bioavailability of Dihydroartemisinin, meether, Artemether, Artesunic Acid and Artelinic Acid in Rats

“…These data demonstrate that DQHS is a major metabolite of AM, AE, AS and AL in the rats after intravenous, intramuscular or intragastric administration. The dose of DQHS required to produce plasma levels equivalent to those of DQHS formed as a metabolite after administration by all three routes of treatment of each of the drug was calculated as previously described (Li & Huempel 1992) using data obtained after administration of DQHS alone.…”

N-Oxygenation of Primary Amines and Hydroxylamines and Retroreduction of Hydroxylamines by Adult Human Liver Microsomes and Adult Human Flavin-Containing Monooxygenase 3

“…Depending on the chemical structure, in vivo administration of oximes may give rise to rapidly hydrolyzed oximes or oximes that are essentially excreted unchanged. Thus, in vivo , administration of the acetylcholinesterase reactivator pyrimodoxine (2-PAM) leads to largely unchanged drug excreted in the urine () while cyclohexanone oxime (an intermediate used in the synthesis of Nylon) is extensively metabolized by hydrolysis and conjugation ( , ). For other oximes, wide species variation in the metabolism of the oxime has been observed ( , ).…”

Water-Soluble Progesterone Analogues Are Effective, Injectable Treatments in Animal Models of Traumatic Brain Injury

“…This was then attached to the PROG skeleton by a oxime linker, which can undergo formal hydrolysis in vivo. 26 A pharmacokinetic experiment was carried out in rats using the iv route of administration to follow the disappearance of 1 and the potential appearance of its related free oxime (2) and/or PROG. The graph in Figure 2A shows that 1 is hydrolyzed rapidly to provide large concentrations of the free oxime 2 and smaller concentrations of PROG.…”

“…The structure of 1 was designed to allow introduction of a solubilizing group that is susceptible to hydrolysis in the bloodstream. This was then attached to the PROG skeleton by a oxime linker, which can undergo formal hydrolysis in vivo . A pharmacokinetic experiment was carried out in rats using the iv route of administration to follow the disappearance of 1 and the potential appearance of its related free oxime ( 2 ) and/or PROG.…”