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- Document type:
- Journal Article
- Author(s):
- Schaller, Stefan J; Alam, Saad M; Mao, Jianren; Zhao, Yanli; Blobner, Manfred; Greenblatt, David J; Martyn, J A Jeevendra
- Title:
- Pharmacokinetics cannot explain the increased effective dose requirement for morphine and midazolam in rats during their extended administration alone or in combination.
- Abstract:
- Chronic administration of morphine and midazolam, alone or in combination, can induce tolerance to their effects. Data showed that co-administration of morphine and midazolam increased effective dose requirement of morphine, exceeding that observed with morphine alone.To elucidate the pharmacokinetic component to the tolerance, we administered midazolam (2 mg/kg) and morphine (10 mg/kg) alone or their combination daily to rats for 12 days followed by a pharmacokinetic study on day 13. On the study day, each animal received a single bolus dose of 5 mg/kg morphine, and 2 mg/kg of midazolam 30 s later. Multiple blood samples were obtained for 6 h. Plasma drug concentrations were assayed by mass spectrometry optimized for small samples.Mean morphine clearance was as follows: 22.2, 27.2, 26.0 and 23.4 l/h per kg in the saline-saline, saline-midazolam, saline-morphine and midazolam-morphine groups, respectively. Corresponding midazolam clearances were 32.8, 23.0, 22.2 and 31.1 l/h per kg. ANOVA indicated no significant differences among the four groups in the clearances, half-lives, and volumes of distribution. Morphine and midazolam clearances were significantly correlated (R = 0.48, P < 0.001).This animal model suggests that altered pharmacokinetics cannot explain tolerance evidenced as increased dose requirement for morphine or midazolam, when administered alone or combination, for extended periods.
- Journal title abbreviation:
- J Pharm Pharmacol
- Year:
- 2017
- Journal volume:
- 69
- Journal issue:
- 1
- Pages contribution:
- 82-88
- Language:
- eng
- Fulltext / DOI:
- doi:10.1111/jphp.12663
- Pubmed ID:
- http://view.ncbi.nlm.nih.gov/pubmed/27891611
- Print-ISSN:
- 0022-3573
- TUM Institution:
- Klinik für Anästhesiologie (DHM)
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