Article Figures & Data
Figures
- Fig. 1.
Relationship between inhibition of APZ turnover (A) and KTZ exposure (B) in HepatoPac incubations (donor 1307). Values represent the mean ± S.D. from three replicates.
- Fig. 2.
Relationship between inhibition of APZ turnover (A) and ERY exposure (B) in HepatoPac incubations (donor 1307). Values represent the mean ± S.D. from three replicates.
- Fig. 3.
Time course of CYP3A activity in the presence and absence of ERY. Values represent the mean of two replicates. (A) The time-dependent changes in 1′OH MDZ activity. (B) The percent remaining CYP3A activity in the presence of ERY relative to the control.
- Fig. 4.
(A) Percent inhibition of APZ CLint by ERY in HepatoPac cultures from multiple donors. (B) ERY CLint from multiple donors at various concentrations of ERY. Values represent the mean ± S.D. of the number of donors used.
- Fig. 5.
CYP1A2 (A), CYP2B6 (B), and CYP3A4 (C) expression in the presence of up to 120 µM ERY, 50 µM OME, and 10 µM RIF. Values are depicted as the mean ± S.D. of three individual biologic replicates. *P < 0.05, statistically significant induction relative to the vehicle control.
- Fig. 6.
(A) Comparison of hepatocyte island morphology in the vehicle-treated control vs. hepatocyte island morphology in the presence of ERY (30 or 60 µM) and APAP (20 mM) 144 hours after start of the incubation. (B) Hepatocellular ALT content over the course of a 144 hours incubation (donor ACR). APAP, acetaminophen.
Tables
Lot Sex Age Cause of Death 1307 Male 31 Anoxia, second to heroin overdose 3121B Female 52 Anoxia, second to cardiac arrest 4202 Female 39 Anoxia, second to cardiac arrest 4297 Female 54 Stroke ACR (10-donor pool) Mixed Sex N/A N/A N/A, not applicable.
Compound MRM Transition Enzyme Alprazolam 309→281 (+) CYP3A Diazepam 285→193 (+) CYP2C19/CYP3A Erythromycin 735→158 (+) CYP3A Estradiol 3-(β-D-glucuronide) 447.0→271.1 (−) UGT1A1, UGT1A3 Ketoconazole 532→489 (+) CYP3A Midazolam 342→324 (+) CYP3A Riluzole 235→166 (+) CYP1A2 Risperidone 411→191 (+) CYP2D6 Tolbutamide 273→155 (+) CYP2C9 Trifluoromethylumbelliferyl β-D-glucuronide 407→231 (+) UGT1A6, UGT1A9, UGT2B7, UGT2B15 Trifluoperazine N-glucuronide 584.0→408.1 (+) UGT1A4 - TABLE 3
Effect of ERY on other CYP450 isoforms
For incubations with diazepam, riluzole, and risperidone, CLint values were derived from the average of two replicates using donor 1307. Tolbutamide CLint values were derived from the average of three replicates each for donors 1307 and ACR. APZ CLint values were derived from the average of two to five replicates each from donors 1307, 3121B, 4202, 4297, and ACR.
Probe Substrate P450 Responsible for Metabolism Percent Metabolized by Isoform Expected Percent Inhibition by 30 µM ERY Observed Percent Inhibition by 30 µM ERY Riluzole CYP2D6 >80 0 7.7 Tolbutamide CYP2C9 >85 0 26 Diazepam CYP3A4/CYP2C19 60/40 60 74 Risperidone CYP2D6 >93 7 21 Alprazolam CYP3A4 >90 100 89 ± 11
