Ciprofloxacin suppresses Cyp3a in mouse liver by reducing lithocholic acid-producing intestinal flora.
Ciprofloxacin (CPX), a new quinolone antibiotic, is reported to reduce CYP3A expression in the liver when administered to rats. The present study investigates whether the reduction in intestinal flora is involved in this reduction of CYP3A. While hepatic Cyp3a11 expression and triazolam metabolic activity were significantly reduced by CPX treatment of SPF mice, no significant changes were seen by CPX treatment of germ-free (GF) mice. Lithocholic acid (LCA)-producing bacteria in the feces as well as hepatic level of taurine conjugate of LCA were significantly reduced in CPX-treated SPF mice. Cyp3a11 expression in GF mice was significantly elevated when treated with LCA, known as an activator of fernesoid X receptor and pregnane X receptor. These results indicate that antibiotics such as CPX, having antimicrobial spectrums against LCA-producing bacteria, possibly cause decrease in LCA in the liver, resulting in lower CYP3A expression. The intestinal flora is reported to be altered also by stress, disease and age etc. The findings of the present study suggest that these changes in intestinal flora may modify CYP expression and contribute to individual differences in pharmacokinetics.
Toda
Takahiro
T
Department of Clinical Pharmacokinetics, Hoshi University, Tokyo, Japan.
Ohi
Kanna
K
Kudo
Toshiyuki
T
Yoshida
Tomoyuki
T
Ikarashi
Nobutomo
N
Ito
Kiyomi
K
Sugiyama
Kiyoshi
K
D000818:Animals; D001419:Bacteria / Q000187:drug effects* / Q000378:metabolism; D002939:Ciprofloxacin / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D007422:Intestines / Q000382:microbiology*; D008095:Lithocholic Acid / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D014229:Triazolam / Q000378:metabolism
D065692:Cytochrome P-450 CYP3A Inhibitors; D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D014229:Triazolam; D002939:Ciprofloxacin; D008095:Lithocholic Acid; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A