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Kinetics of drug action in disease states. XXXVI: Effect of cyclosporine on the pharmacodynamics and pharmacokinetics of a barbiturate (heptabarbital) in rats.

Abstract：

:Pretreatment with cyclosporine reportedly prolongs the effect of certain general anesthetics in humans and the sleeping time of mice after pentobarbital administration. This investigation was designed to determine the mechanism(s) of the cyclosporine-barbiturate interaction. Adult female Wistar rats received cyclosporine (50 mg/kg im) or saline solution daily for 3 days. On the third day, they were injected with heptabarbital (45 mg/kg iv). Other cyclosporine-treated and control groups were infused with heptabarbital until they lost their righting reflex. Treatment for 3 d with cyclosporine was associated with decreased rectal temperature, decreased magnesium concentrations in serum and CSF, increased serum creatinine and urea nitrogen concentrations, elevated serum aspartate aminotransferase activity and total bilirubin concentration, decreased serum total protein concentration, and increased hematocrit. These physiologic changes are consistent with the clinically observed hypomagnesemia, nephrotoxicity, and hepatotoxicity in patients treated with cyclosporine. Control rats slept for 90 +/- 14 min (mean +/- SD, n = 9) after heptabarbital injection, whereas cyclosporine-pretreated rats slept for 154 +/- 22 min. Compared with controls, cyclosporine-pretreated rats awoke (after heptabarbital injection) and went to sleep (after heptabarbital infusion) with significantly lower barbiturate concentrations in serum and CSF. Pretreatment with a single 60-mg/kg im dose of cyclosporine 2 h before heptabarbital infusion caused no significant biochemical changes approximately 160 min later, except for elevated serum aspartate aminotransferase (which occurred also after injection of the surfactant-containing vehicle) and serum bilirubin. Again, heptabarbital concentrations at onset of sleep (loss of righting reflex) in serum, brain, and CSF of cyclosporine-treated rats were significantly lower than in saline-treated controls.(ABSTRACT TRUNCATED AT 250 WORDS)

journal_name

J Pharm Sci

journal_title

Journal of pharmaceutical sciences

authors

Hoffman A,Levy G

doi

10.1002/jps.2600790106

subject

Has Abstract

pub_date

1990-01-01 00:00:00

pages

19-22

issue

eissn

0022-3549

issn

1520-6017

pii

S0022-3549(15)48135-3

journal_volume

pub_type

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Kinetics of drug action in disease states. XXXVI: Effect of cyclosporine on the pharmacodynamics and pharmacokinetics of a barbiturate (heptabarbital) in rats.