Induction of influx and efflux transporters and cytochrome P450 3A4 in primary human hepatocytes by rifampin, rifabutin, and rifapentine

Beth Williamson, Kelly E Dooley, Yuan Zhang, David J Back, Andrew Owen, Beth Williamson, Kelly E Dooley, Yuan Zhang, David J Back, Andrew Owen

Abstract

Rifampin is a potent inducer of cytochrome P450 (CYP) enzymes and transporters. Drug-drug interactions during tuberculosis treatment are common. Induction by rifapentine and rifabutin is understudied. Rifampin and rifabutin significantly induced CYP3A4 (80-fold and 20-fold, respectively) in primary human hepatocytes. The induction was concentration dependent. Rifapentine induced CYP3A4 in hepatocytes from 3 of 6 donors. Data were also generated for ABCB1, ABCC1, ABCC2, organic anion-transporting polypeptide 1B1 (OATP1B1), and OATP1B3. This work serves as a basis for further study of the extent to which rifamycins induce key metabolism and transporter genes.

Figures

Fig 1
Fig 1
Relative gene expression of cytochrome P450 isoenzyme 3A4 and ABCB1 in primary hepatocytes when incubated with rifampin (RIF), rifabutin (RBT), or rifapentine (RPT) at 0, 0.5, 5, and 10 μM. Data were normalized to results for GAPDH housekeeping gene and for control primary hepatocytes (0 μM) using the comparative CT method (CT = 2−ΔΔCT). Tukey box plot represents the means and interquartile ranges (IQR) (n = 6 donors completed in triplicate), with boxes showing IQR and whiskers representing <1.5 × IQR. Data outside 1.5 × IQR are labeled as outliers (•). An asterisk indicates a significant difference from the control (0 μM) by paired t test or Wilcoxon signed-rank test (P < 0.05).

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