Ethanol inhibits the metabolism of oseltamivir to its active metabolite

Purpose: Human carboxylesterase-1 (hCE1) plays an important role in the metabolism of many commonly used drugs containing ester groups. Unlike drugs metabolized by cytochrome-P450 enzymes, it remains unclear whether metabolic inhibition of hCE1 is a potential mechanism for drug-drug interactions for medications that are substrates for this enzyme. Ethanol inhibits hCE1 in-vitro and in animal models but its effects on hCE1 substrates in humans are uncertain. This study uses the ester prodrug oseltamivir (OS) as a probe in humans to determine if ethanol inhibits hCE1-mediated hydrolysis of OS to the active neuraminidase inhibitor metabolite, oseltamivir carboxylic acid (OSA). 

Methods:   Healthy human volunteers (n=9) received 150 mg oral OS (Tamiflu¨) alone and with ethanol on separate study days with blood samples collected at various times for analysis of OS and OSA by LC/MS/MS. OS and OSA pharmacokinetic parameters were estimated using standard noncompartmental analysis.

Results: The effects of ethanol on OSA pharmacokinetics are shown in the table below. Ethanol did not affect OS Cmax, Tmax, AUC_0-6hr, or AUC_inf.

OSA Pharmacokinetic Parameters	Oseltamivir	Oseltamivir + EtOH
Cmax (ng/ml)	477 ± 59	432 ± 68*
Tmax (hours)	4.4 ± 0.5	6.2 ± 1.2*
AUC0-6hr (ng/ml*h)	1759 ± 379	1437 ± 368*
AUC0-6hr Ratio (ng/ml*h)	6.9 ± 1.8	4.9 ± 1.2*
AUC0-inf (ng/ml*h)	6838 ± 593	6755 ± 840
AUC0-inf Ratio (ng/ml*h)	22.6 ± 4.6	19.3 ± 5.4*

*p<0.05; AUC_0-6 Ratio = OSA AUC_0-6hr Ö OS AUC_0-6hr; AUC_inf Ratio = OSA AUC_inf Ö OS AUC_inf Data are mean ± standard deviation

Conclusion: Ethanol inhibits the conversion of OS to the active OSA metabolite and therefore could affect the antiviral activity of OS (Tamiflu¨). Ethanol-mediated inhibition of hCE1 hydrolysis may be an important mechanism for drug-drug interactions and affect the safety and efficacy of the many medications that are substrates for this enzyme.