Abstract | OBJECTIVE: DESIGN AND METHODS: Adult male Sprague-Dawley (SD) rats received single intravenous (1-10 mg/kg) or oral (5-10 mg/kg) bolus doses of EMA200, EMA300, EMA400 or EMA401 (S-enantiomer of EMA400). Blood samples were collected immediately pre-dose and at specified times over a 12- to 24-hour post-dosing period. Liquid chromatography tandem mass spectrometry was used to measure plasma drug concentrations. Efficacy was assessed in adult male SD rats with a unilateral chronic constriction injury (CCI) of the sciatic nerve. RESULTS: After intravenous administration in rats, mean (±standard error of the mean) plasma clearance for EMA200, EMA300, EMA400, and EMA401 was 9.3, 6.1, 0.7, and 1.1 L/hour/kg, respectively. After oral dosing, the dose-normalized systemic exposures of EMA400 and EMA401 were 20- to 30-fold and 50- to 60-fold higher than that for EMA300 and EMA200, respectively. The oral bioavailability of EMA400 and EMA401 was similar at ∼30%, whereas it was only 5.9% and 7.1% for EMA200 and EMA300, respectively. In CCI rats, single intraperitoneal bolus doses of EMA200, EMA300, and EMA400 evoked dose-dependent pain relief. The pain relief potency rank order in CCI rats was EMA400 > EMA300 > EMA200 in agreement with the dose-normalized systemic exposure rank order in SD rats. CONCLUSION:
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Authors | Maree T Smith, Bruce D Wyse, Stephen R Edwards |
Journal | Pain medicine (Malden, Mass.)
(Pain Med)
Vol. 14
Issue 5
Pg. 692-705
(May 2013)
ISSN: 1526-4637 [Electronic] England |
PMID | 23489258
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Wiley Periodicals, Inc. |
Chemical References |
- Analgesics
- Angiotensin II Type 2 Receptor Blockers
- Receptor, Angiotensin, Type 2
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Topics |
- Administration, Oral
- Analgesics
(administration & dosage, pharmacokinetics)
- Angiotensin II Type 2 Receptor Blockers
(administration & dosage, pharmacokinetics)
- Animals
- Dose-Response Relationship, Drug
- Injections, Intravenous
- Male
- Neuralgia
(diagnosis, drug therapy, metabolism)
- Pain Measurement
(drug effects)
- Protein Binding
- Rats
- Rats, Sprague-Dawley
- Receptor, Angiotensin, Type 2
(metabolism)
- Treatment Outcome
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