PI-60Effect of hemodialysis on hepatic CYP3A4 activity

Abstract

BACKGROUND Altered drug metabolism has been demonstrated in patients with end‐stage renal disease (ESRD). The aim of this study was to evaluate the acute effect of hemodialysis (HD) on CYP3A4 activity. METHODS 12 ESRD patients undergoing chronic HD and 12 matched control subjects participated. Hepatic CYP3A4 activity was assessed using the 14C‐erythromycin breath test (EBT). The EBT was administered two hours pre‐ and repeated two hours post‐hemodialysis and once in controls. Breath samples were collected at baseline and various time points up to 120 min after dosing, and then analyzed for 14C using scintillation counting. The traditional 20‐min flux measure and the novel 1/Tmax parameter were determined. RESULTS The flux of 14CO2 at the 20‐minute time point, expressed as the % of the administered dose exhaled per hour, increased by 27% post‐dialysis, from 2.34±0.8 to 2.98±1.04 (p<0.05). Pre‐ and post‐HD values were similar to those observed in control subjects (2.70±0.59; p=NS). Pre‐ and post‐HD 1/Tmax values approached but did not achieve a statistically significance difference (0.056±0.01 and 0.067±0.02, respectively, p=0.07). Pre‐HD 1/Tmax was lower than control (0.064±0.01, p<0.05) and normalized after dialysis. CONCLUSIONS These results suggest that hemodialysis acutely improves hepatic CYP3A4 activity and indicate that increased diligence is warranted when prescribing CYP3A substrates to ESRD patients. Clinical Pharmacology & Therapeutics (2005) 79, P23–P23; doi:

Simultaneous Assessment of Hepatic Transport and Metabolism Pathways with a Single Probe Using Individualized PBPK Modeling of 14CO2 Production Rate Data

“…Clinical Data Sources. The 14 CO 2 production rate data were obtained from a prospective cohort study in which the ERMBT was administered to 12 healthy Caucasian subjects (seven male) (Nolin et al, 2006b). Briefly, a single 0.074 mmol (0.04 mg, 3 mCi) dose of [ 14 C-N-methyl] erythromycin (Metabolic Solutions Inc., Nashua, NH) was intravenously administered and breath samples were collected immediately before receiving the dose and at 5,10,15,20,30,40,50,60,90, and 120 minutes postdosing as previously described (Nolin et al, 2006a).…”