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 norethisterone-3-oxime acetate (NETO-AC) were given intravenously or orally through 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 1/2 ka, t 1/2 alpha and t 1/2 beta with standard deviation for oral administration were 0.21 +/- 0.08 (h), 1.28 +/- 0.31 (h) and 10.01 +/- 4.59 (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 metabolized 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 appeared 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.(ABSTRACT TRUNCATED AT 250 WORDS)