Anti-Influenza Prodrug Oseltamivir Is Activated by Carboxylesterase Human Carboxylesterase 1, and the Activation Is Inhibited by Antiplatelet Agent Clopidogrel

Abstract

Oseltamivir is the main medicine recommended by the World Health Organization in anticipation of next influenza pandemic. This anti-influenza viral agent is an ester prodrug, and the antiviral activity is achieved by its hydrolytic metabolite: oseltamivir carboxylate. In this study, we report that the hydrolytic activation is catalyzed by carboxylesterase human carboxylesterase (HCE) 1. Liver microsomes rapidly hydrolyzed oseltamivir, but no hydrolysis was detected with intestinal microsomes or plasma. The overall rate of the hydrolysis varied among individual liver samples and was correlated well with the level of HCE1. Recombinant HCE1 but not HCE2 hydrolyzed this prodrug and produced similar kinetic parameters as the liver microsomes. Several HCE1 natural variants differed from the wildtype enzyme on the hydrolysis of oseltamivir. In the presence of antiplatelet agent clopidogrel, the hydrolysis of oseltamivir was inhibited by as much as 90%

A population‐based study of the drug interaction between clopidogrel and angiotensin converting enzyme inhibitors

“…CES1 is involved in the bio‐activation of prodrug ACE inhibitors and is competitively inhibited by clopidogrel in vitro 19, 20. A recent study by Kristensen and colleagues examined the potential clopidogrel–ACE inhibitor drug interaction and observed a modest increase in the risk of adverse cardiac events (acute myocardial infarction, cardiovascular death or stroke) in patients prescribed clopidogrel with an ACE inhibitor relative to those prescribed an ACE inhibitor alone (hazard ratio 1.12, 95% CI 1.06, 1.19) 23.…”

“…First, clopidogrel concentrations used in drug inhibition studies (20–50 µ m ) are generally much higher than those achieved in vivo after a 75 mg oral dose (2.2–2.5 ng ml –1 ) 19, 20. Second, clopidogrel is highly protein bound (>98%) and unbound clopidogrel will constitute only a small fraction of total drug concentrations.…”

“…Importantly, CES1 can be inhibited by other medications and substrates, including clopidogrel 19, 20, 21, 22. Clopidogrel‐mediated inhibition of this enzyme has been shown to interfere with the bio‐activation of several prodrugs, including oseltamivir and others 19, 20.…”

“…Clopidogrel‐mediated inhibition of this enzyme has been shown to interfere with the bio‐activation of several prodrugs, including oseltamivir and others 19, 20. Recent findings of Kristensen and colleagues also suggest that ACE inhibitors may competitively inhibit CES1, thereby shunting clopidogrel towards CYP‐mediated bioactivation and increasing the concentration of active metabolites in vitro 23.…”

Carboxylesterases from the seeds of an underutilized legume, Mucuna pruriens; isolation, purification and characterization

“…Other significant functions of the carboxylesterases include metabolism and subsequent detoxification of many agrochemicals, pharmaceuticals (Redinbo and Potter, 2005;Potter and Wadkins, 2006), metabolism of a number of therapeutics (Williams, 1985), including the cholesterol-lowering drug, lovastatin (Tang and Kalow, 1995), the antiinfluenza drug, Oseltamivir (Tamiflu) (Shi et al, 2006), the narcotic analgesic meperidine (Demerol) (Zhang et al, 1999), cocaine and heroin (Pindel et al, 1997), and resolution of racemic mixtures by transesterification, or the enantioselective hydrolysis of esters for obtaining optically pure compounds (Bornscheuer, 2002). Carboxylesterase activity is also used extensively in soft-and pro-drug design (Bodor and Buchwald, 2000, 2003.…”