Kinetics of Drug Action in Disease States. XXXVI: Effect of Cyclosporine on the Pharmacodynamics and Pharmacokinetics of a Barbiturate (Heptabarbital) in Rats
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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)