Influence of rifampicin on the expression and function of human intestinal cytochrome P450 enzymes.
OBJECTIVE
To investigate the potential induction by rifampicin of intestinal CYP2C8, CYP2C9, CYP2D6 and CYP3A4 using preparations of human enterocytes.


METHODS
Using a multilumen perfusion catheter shed human enterocytes were collected from 6 healthy subjects before and after 10 days of 600 mg day(-1) oral rifampicin administration. The protein expression of CYP2C8, CYP2C9, CYP2D6 and CYP3A4 as well as that of CYP3A4 mRNA was determined using Western blotting and RT-PCR, respectively.


RESULTS
CYP3A4 mRNA expression in shed enterocytes increased from 74.6 +/- 44.2 to 143.2 +/- 68.4 a.u. (P < 0.05, 95% CI: 21.8-115.3). Expression of CYP2C8 and CYP2C9 increased from 5.1 +/- 0.9 to 10.4 +/- 2.3 pmol mg(-1) protein (P < 0.01, 95% CI: 2.8-7.7) and from 4.2 +/- 1.4 to 5.7 +/- 1.1 pmol mg(-1) protein (P < 0.01, 95% CI: 0.6-2.4), respectively. No significant difference in CYP2D6 expression before and during rifampicin intake was observed. Rifampicin administration also resulted in a significant induction of CYP3A4 protein (34.1 +/- 10.7 vs. 113.9 +/- 31.1 pmol mg(-1) protein (P < 0.001, 95% CI: 51.8-107.6)). Ex vivo incubation of enterocyte homogenates with verapamil resulted in a significantly increased production of the metabolites formed via CYP3A4 (D-617: 125.9 +/- 118.8 vs. 277.2 +/- 145.5 pmol min(-1) mg(-1) protein (P < 0.05, 95% CI: 30.1-272.5); norverapamil: 113.0 +/- 57.9 vs. 398.4 +/- 148.2 pmol min(-1) mg(-1) protein (P < 0.05, 95% CI: 47.2-523.6)).


CONCLUSIONS
Our findings indicate that shed enterocytes are a useful tool to study the expression, regulation and function of drug metabolizing enzymes. Induction of intestinal CYP2C8 and CYP2C9 might contribute in part to rifampicin - mediated drug interactions, in addition to their hepatic counterparts and intestinal and hepatic CYP3A4.
Glaeser
H
H
Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany. hartmut.glaeser@vanderbilt.edu
Drescher
S
S
Eichelbaum
M
M
Fromm
M F
MF
D000284:Administration, Oral; D000328:Adult; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D020895:Enterocytes / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D012293:Rifampin