Pharmacodynamic studies with (-)-3-phenoxy-N-methylmorphinan in rats
| Autor: | Karen Carter, Arthur C. Loh, Alice J. Szuna, Franz-Josef Leinweber, Morton A. Schwartz, Jerry Sepinwall |
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| Rok vydání: | 1982 |
| Předmět: |
Pharmacology
Male medicine.medical_specialty Gastrointestinal tract Analgesics Dose-Response Relationship Drug Chemistry Analgesic 3-phenoxy-N-methylmorphinan Brain Rats Inbred Strains Absorption (skin) Prodrug Biochemistry Rats Endocrinology Internal medicine Pharmacodynamics Levorphanol medicine Animals Intestinal Mucosa Active metabolite medicine.drug |
| Zdroj: | Biochemical pharmacology. 31(4) |
| ISSN: | 0006-2952 |
| Popis: | Analgesia and brain and plasma concentrations of (−)-3-phenoxy- N -methylmorphinan (PMM) and its metabolites were determined in rats administered 50 mg/kg of 3 H-labeled PMM p.o., an approximate ED 50 . Unchanged PMM and two active metabolites, levorphanol and a different phenol, p -hydroxylated on the 3-phenoxy group ( p OH-PMM), were present in brain at concentrations greater than in plasma. Analgesia was observed from 1 to 6 hr and was associated with brain concentrations of 400–1400 ng/g of PMM, 190–300 ng/g of p OH-PMM, and 16–27 ng/g of levorphanol. The presence of 58% of the administered dose as unchanged PMM in the gastrointestinal tract at 6 hr may reflect slow absorption and explain the persisting brain concentrations of PMM and its metabolites as well as the prolonged analgesia. Analgesia may have been due to the presence in brain of only PMM, p OHPMM or levorphanol, or to the combined activity of two or three of these substances. Administration of the approximate ED 50 of 3 H-labeled levorphanol (0.1 mg/kg, s.c., or 6 mg/kg, p.o.) resulted in brain levorphanol concentrations (11–18 ng/g) close to those observed when PMM was administered p.o. at 50 mg/kg. After administration of an approximate subcutaneous ED 50 of [ 3 H ]p OH-PMM of 24 mg/kg, the brains contained p OH-PMM (1500–4100 ng/g) and levorphanol (60–100 ng/g); these levorphanol concentrations were higher than those found after administration of the approximate ED 5 of PMM or levorphanol. The findings indicate that brain levorphanol concentrations resulting from administration of PMM or p OH-PMM to rats may account for the analgesic activity observed, i.e. that PMM and p OH-PMM may act as prodrugs for levorphanol. |
| Databáze: | OpenAIRE |
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