H Glaeser1, S Drescher, M Eichelbaum, M F Fromm. 1. Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany. hartmut.glaeser@vanderbilt.edu
Abstract
AIMS: 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)). CONCLUSION: 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.
AIMS: 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)). CONCLUSION: 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.
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