Pharmacokinetic studies of norethisterone-3-oxime and norethisterone-3-oxime acetate in Rhesus monkey

Abstract

After [6,7-³H]-labelled norethisterone-3-oxime (NETO) and nore-thisterone-3-oxime acetate (NETO-AC) were given intravenously or orally througn a nasal tube with 1 mg of respective unlabelled steroid to Rhesus monkey, serum samples were collected at various periods, and radioactivity was counted with or without reverse-phase HPLC separation in advance. Pharmacokinetics of NETO and NETO-AC were compared with those of norethisterone (NET) and norethisterone acetate (NET-AC)-(respectively which were studied in a similar experimental design. The results indicated that the serum concentration-time curve of NETO and NET could be adequately described by a two-compartment model. Average t_1/2ka, t_1/2α and t_1/2β with standard deviation for oral administration were 0.21±0.08 (h), 1.28±0.31 (h) and 10.0±U4.59 (h) for NET and 0.37±0.81 (h), 0.90±0.26 (h) and 8.55±2.21 (h) for NETO respectively. NETO metabolized to NET which had a similar serum profile with its precursor. NET-AC also met:-bolized to NET, but more rapidly. It disappeared from blood 8–12 h after nasal feeding. NETO-AC was non-detectable at all when given orally because it metabolized immediately and extensively in the animal body. Its major metabolites, NETO, NET and NET-AC already appealed in the first blood sample drawn 15 min after administration. NETO-AC, when injected intravenously, declined abruptly and could not be detected 4 h later. Among the metabolites, only the deacetylated products (NET and NETO) reached relatively higher levels and sustained longer in blood. The absolute bioavailability (x± Sx) for NETO was 39.14±11.40 (%) and 49.96±24.24 (%) for NETO-AC. No statistically significant differences between the main pharmacokinetic parameters of NETO and NET as well as NETO-AC and NET-AC were found.

Keywords

pharmacokinetics / norethisterone-3-oxime / norethisterone-3-oxime acetate / Rhesus monkey / HPLC

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