Changes of midazolam pharmacokinetics in Wistar rats treated with lipopolysaccharide: relationship between total CYP and CYP3A2.
It has been reported that infection interferes with drug metabolism, resulting in changes in pharmacokinetics. In this study, we investigated the effects of lipopolysaccharide (LPS) on hepatic total cytochrome P450 (CYP), CYP3A2, and CYP2C11 contents in a transient, LPS-induced, endotoxemia model of rats. In addition, to assess the effects on CYP3A2 activities, the pharmacokinetics of midazolam (CYP3A2 substrate) and 1-OH-midazolam (metabolite of midazolam) were investigated. Hepatic total CYP contents were significantly low until day 3 (P < 0.05) but returned to the control level on day 5. Hepatic CYP3A2 contents were significantly decreased on day 1 until day 5 (P < 0.05) but returned to the control level on day 7. Hepatic CYP2C11 contents were continuously low until day 7, and lowest on day 3. The AUC of 1-OH-midazolam was significantly decreased on day 1 after LPS administration (P < 0.01). In conclusion, LPS (5 mg/kg) challenge decreased hepatic total CYP, CYP3A2, and CYP2C11 contents and also decreased the activities of hepatic CYP3A2. It took at least 7 days for hepatic total CYP and CYP3A2 to recover to control levels, and it was suggested that the changes of hepatic total CYP contents might correlate with those of hepatic CYP3A2 contents and activities. Additionally, it is shown that their changes might reflect the recovery process from inflammation.
Kato
Ryuji
R
Laboratory of Clinical Pharmacy and Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan.
Yamashita
Satoshi
S
Moriguchi
Jun
J
Nakagawa
Machiko
M
Tsukura
Yuri
Y
Uchida
Kagehiro
K
Amano
Fumio
F
Hirotani
Yoshihiko
Y
Ijiri
Yoshio
Y
Tanaka
Kazuhiko
K
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000032:analysis / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis* / Q000187:drug effects; D000072467:Cytochrome P450 Family 2; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000097:blood; D008070:Lipopolysaccharides / Q000276:immunology*; D008099:Liver / Q000201:enzymology / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism*; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics*; D009569:Nitric Oxide / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D039181:Steroid 16-alpha-Hydroxylase / Q000032:analysis / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D008874:Midazolam