Effects of glucocorticoids on pharmacokinetics and pharmacodynamics of midazolam in rats

Minoru Watanabe, Tomonori Tateishi, Masako Asoh, Hironori Nakura, Masami Tanaka, Toshio Kumai, Shinichi Kobayashi

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

We investigated the effect of dexamethasone (80 mg/kg per day for 2 days) and prednisolone (600 mg/kg per day for 2 days, equivalent to dexamethasone for glucocorticoid (GC) potency) on both pharmacokinetics and pharmacodynamics of midazolam (MDZ), a substrate for cytochrome P450 (CYP) 3A, in 8-week-old male Sprague-Dawley rats. Animals received a single injection of MDZ (pharmacokinetic study, 10 mg/kg; pharmacodynamic study, 55.5 mg/kg) in the tail vein 24 h after the last dose of GC or placebo. The elimination half-life (t1/2) and the area under the concentration-time curve of MDZ were significantly reduced by pretreatment with dexamethasone to 58.9% and 44.7% of the control value, respectively, and the clearance of MDZ was significantly increased by dexamethasone. Similar changes observed by prednisolone pretreatment did not reach significance. The t1/2 of the dexamethasone pretreatment group (14.4±0.7 min) was significantly shorter than that of the prednisolone group (20.9±1.5 min). The amount of CYP3A2 protein and the activity of erythromycin N-demethylase were significantly increased by dexamethasone and prednisolone pretreatments, but dexamethasone showed a greater effect than prednisolone. Sleeping time was significantly shortened by dexamethasone and prednisolone pretreatment to 38.7% and 57.1% of control value, respectively. The current study demonstrates that the anesthetic effect of MDZ would be reduced in patients treated with dexamethasone or prednisolone, and that the CYP3A induction was greater by dexamethasone than by prednisolone, implying that the potency of CYP3A induction may differ among GCs even when GC activity is the same.

Original languageEnglish
Pages (from-to)1685-1692
Number of pages8
JournalLife Sciences
Volume63
Issue number19
DOIs
Publication statusPublished - Oct 2 1998
Externally publishedYes

Fingerprint

Pharmacodynamics
Pharmacokinetics
Midazolam
Dexamethasone
Glucocorticoids
Rats
Prednisolone
Cytochrome P-450 CYP3A
Sprague Dawley Rats
Half-Life
Anesthetics
Tail
Veins
Animals
Placebos

Keywords

  • CYP3A
  • Glucocorticoid
  • Midazolam
  • Pharmacokinetic parameter
  • Sleeping time

ASJC Scopus subject areas

  • Pharmacology

Cite this

Watanabe, M., Tateishi, T., Asoh, M., Nakura, H., Tanaka, M., Kumai, T., & Kobayashi, S. (1998). Effects of glucocorticoids on pharmacokinetics and pharmacodynamics of midazolam in rats. Life Sciences, 63(19), 1685-1692. https://doi.org/10.1016/S0024-3205(98)00440-8

Effects of glucocorticoids on pharmacokinetics and pharmacodynamics of midazolam in rats. / Watanabe, Minoru; Tateishi, Tomonori; Asoh, Masako; Nakura, Hironori; Tanaka, Masami; Kumai, Toshio; Kobayashi, Shinichi.

In: Life Sciences, Vol. 63, No. 19, 02.10.1998, p. 1685-1692.

Research output: Contribution to journalArticle

Watanabe, M, Tateishi, T, Asoh, M, Nakura, H, Tanaka, M, Kumai, T & Kobayashi, S 1998, 'Effects of glucocorticoids on pharmacokinetics and pharmacodynamics of midazolam in rats', Life Sciences, vol. 63, no. 19, pp. 1685-1692. https://doi.org/10.1016/S0024-3205(98)00440-8
Watanabe, Minoru ; Tateishi, Tomonori ; Asoh, Masako ; Nakura, Hironori ; Tanaka, Masami ; Kumai, Toshio ; Kobayashi, Shinichi. / Effects of glucocorticoids on pharmacokinetics and pharmacodynamics of midazolam in rats. In: Life Sciences. 1998 ; Vol. 63, No. 19. pp. 1685-1692.
@article{cab7904802ae4370816d669d5ec0160f,
title = "Effects of glucocorticoids on pharmacokinetics and pharmacodynamics of midazolam in rats",
abstract = "We investigated the effect of dexamethasone (80 mg/kg per day for 2 days) and prednisolone (600 mg/kg per day for 2 days, equivalent to dexamethasone for glucocorticoid (GC) potency) on both pharmacokinetics and pharmacodynamics of midazolam (MDZ), a substrate for cytochrome P450 (CYP) 3A, in 8-week-old male Sprague-Dawley rats. Animals received a single injection of MDZ (pharmacokinetic study, 10 mg/kg; pharmacodynamic study, 55.5 mg/kg) in the tail vein 24 h after the last dose of GC or placebo. The elimination half-life (t1/2) and the area under the concentration-time curve of MDZ were significantly reduced by pretreatment with dexamethasone to 58.9{\%} and 44.7{\%} of the control value, respectively, and the clearance of MDZ was significantly increased by dexamethasone. Similar changes observed by prednisolone pretreatment did not reach significance. The t1/2 of the dexamethasone pretreatment group (14.4±0.7 min) was significantly shorter than that of the prednisolone group (20.9±1.5 min). The amount of CYP3A2 protein and the activity of erythromycin N-demethylase were significantly increased by dexamethasone and prednisolone pretreatments, but dexamethasone showed a greater effect than prednisolone. Sleeping time was significantly shortened by dexamethasone and prednisolone pretreatment to 38.7{\%} and 57.1{\%} of control value, respectively. The current study demonstrates that the anesthetic effect of MDZ would be reduced in patients treated with dexamethasone or prednisolone, and that the CYP3A induction was greater by dexamethasone than by prednisolone, implying that the potency of CYP3A induction may differ among GCs even when GC activity is the same.",
keywords = "CYP3A, Glucocorticoid, Midazolam, Pharmacokinetic parameter, Sleeping time",
author = "Minoru Watanabe and Tomonori Tateishi and Masako Asoh and Hironori Nakura and Masami Tanaka and Toshio Kumai and Shinichi Kobayashi",
year = "1998",
month = "10",
day = "2",
doi = "10.1016/S0024-3205(98)00440-8",
language = "English",
volume = "63",
pages = "1685--1692",
journal = "Life Sciences",
issn = "0024-3205",
publisher = "Elsevier Inc.",
number = "19",

}

TY - JOUR

T1 - Effects of glucocorticoids on pharmacokinetics and pharmacodynamics of midazolam in rats

AU - Watanabe, Minoru

AU - Tateishi, Tomonori

AU - Asoh, Masako

AU - Nakura, Hironori

AU - Tanaka, Masami

AU - Kumai, Toshio

AU - Kobayashi, Shinichi

PY - 1998/10/2

Y1 - 1998/10/2

N2 - We investigated the effect of dexamethasone (80 mg/kg per day for 2 days) and prednisolone (600 mg/kg per day for 2 days, equivalent to dexamethasone for glucocorticoid (GC) potency) on both pharmacokinetics and pharmacodynamics of midazolam (MDZ), a substrate for cytochrome P450 (CYP) 3A, in 8-week-old male Sprague-Dawley rats. Animals received a single injection of MDZ (pharmacokinetic study, 10 mg/kg; pharmacodynamic study, 55.5 mg/kg) in the tail vein 24 h after the last dose of GC or placebo. The elimination half-life (t1/2) and the area under the concentration-time curve of MDZ were significantly reduced by pretreatment with dexamethasone to 58.9% and 44.7% of the control value, respectively, and the clearance of MDZ was significantly increased by dexamethasone. Similar changes observed by prednisolone pretreatment did not reach significance. The t1/2 of the dexamethasone pretreatment group (14.4±0.7 min) was significantly shorter than that of the prednisolone group (20.9±1.5 min). The amount of CYP3A2 protein and the activity of erythromycin N-demethylase were significantly increased by dexamethasone and prednisolone pretreatments, but dexamethasone showed a greater effect than prednisolone. Sleeping time was significantly shortened by dexamethasone and prednisolone pretreatment to 38.7% and 57.1% of control value, respectively. The current study demonstrates that the anesthetic effect of MDZ would be reduced in patients treated with dexamethasone or prednisolone, and that the CYP3A induction was greater by dexamethasone than by prednisolone, implying that the potency of CYP3A induction may differ among GCs even when GC activity is the same.

AB - We investigated the effect of dexamethasone (80 mg/kg per day for 2 days) and prednisolone (600 mg/kg per day for 2 days, equivalent to dexamethasone for glucocorticoid (GC) potency) on both pharmacokinetics and pharmacodynamics of midazolam (MDZ), a substrate for cytochrome P450 (CYP) 3A, in 8-week-old male Sprague-Dawley rats. Animals received a single injection of MDZ (pharmacokinetic study, 10 mg/kg; pharmacodynamic study, 55.5 mg/kg) in the tail vein 24 h after the last dose of GC or placebo. The elimination half-life (t1/2) and the area under the concentration-time curve of MDZ were significantly reduced by pretreatment with dexamethasone to 58.9% and 44.7% of the control value, respectively, and the clearance of MDZ was significantly increased by dexamethasone. Similar changes observed by prednisolone pretreatment did not reach significance. The t1/2 of the dexamethasone pretreatment group (14.4±0.7 min) was significantly shorter than that of the prednisolone group (20.9±1.5 min). The amount of CYP3A2 protein and the activity of erythromycin N-demethylase were significantly increased by dexamethasone and prednisolone pretreatments, but dexamethasone showed a greater effect than prednisolone. Sleeping time was significantly shortened by dexamethasone and prednisolone pretreatment to 38.7% and 57.1% of control value, respectively. The current study demonstrates that the anesthetic effect of MDZ would be reduced in patients treated with dexamethasone or prednisolone, and that the CYP3A induction was greater by dexamethasone than by prednisolone, implying that the potency of CYP3A induction may differ among GCs even when GC activity is the same.

KW - CYP3A

KW - Glucocorticoid

KW - Midazolam

KW - Pharmacokinetic parameter

KW - Sleeping time

UR - http://www.scopus.com/inward/record.url?scp=0032476161&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032476161&partnerID=8YFLogxK

U2 - 10.1016/S0024-3205(98)00440-8

DO - 10.1016/S0024-3205(98)00440-8

M3 - Article

C2 - 9806224

AN - SCOPUS:0032476161

VL - 63

SP - 1685

EP - 1692

JO - Life Sciences

JF - Life Sciences

SN - 0024-3205

IS - 19

ER -