Time-dependent effects of dexamethasone administration on the suppression of plasma hydrocortisone, assessed with a pharmacokinetic model

Abstract

The influence of the time of dexamethasone (DEX) administration (0.5 mg i.v.) on the suppression of plasma hydrocortisone (HC) was investigated in six healthy subjects, by comparing dosage times of 8 and 20 hr. To estimate HC production after DEX administration a pharmacokinetic model was developed and applied to the time course of plasma HC. This model was based on the assumption that HC production could be described as a continuous i.v. infusion, that stops and starts instantaneously. After DEX at 8 hr, HC production was reduced instantaneously to a minimum level and HC disappeared rapidly from plasma with an elimination half-life of 1.32 +/- 0.28 hr (mean +/- S.D.). Almost complete suppression of HC production lasted for 20 hr. The nocturnal increase in HC production at 20 hr after DEX administration was still attenuated compared to the preceding night. After DEX administration at 20 hr, plasma HC was lower than control for about 20 hr, but it was not reduced to the very low level observed after DEX dosage in the morning. Approximately 20 hr after dosage of DEX at 20 hr, HC production seemed to follow the normal diurnal variation of the control values again. To explain the difference in HC suppression by DEX at different dosage times, we constructed a curve describing the relationship between DEX concentration and suppression of the sudden increase in HC production during the night. This curve indicates that HC suppression by DEX could be completely dependent on DEX concentration, without a DEX independent circadian variation.