The influence of ethanol on drug metabolism and disposition via carboxylesterase-mediated transesterification

Carboxylesterase enzymes hydrolyze a wide variety of ester-containing xenobiotics to yield carboxylic acids. It has now been determined that these enzymes catalyze the ethanolic transesterification of ester-containing compounds. Perhaps the most widely publicized and significant transesterification reaction is the conversion of cocaine (COC) to cocaethylene (CE) in the presence of ethanol. The formed CE possesses pharmacological activity, nearly identical to COC, a longer half-life and is more toxic than COC. We hypothesized that the transesterification of COC to CE is not unique and other compounds containing carboxyl ester groups might undergo transesterification in the presence of ethanol. Both methyl-ester and ethyl-ester-containing compounds were investigated using an in vitro and in vivo paradigm. Cocaethylene (CE), meperidine (MEP) and methylphenidate (MPH) are all compounds containing carboxyl ester groups which are extensively metabolized to carboxylic acids. Excised liver from male Sprague-Dawley rats were homogenized and centrifuged at 9,000g and the S9 fraction collected. Each drug investigated was separately incubated with S9 at 37°C with and without ethanol or ²H₆-ethanol. Parent drugs and predicted ethyl-ester formation products were assayed via gas chromatography/mass spectrometry (GC/MS). The experiments were repeated in vivo in rats. Animals were dosed with drug in the absence or presence of ethanol or ²H₆-ethanol. Plasma was collected and assayed for parent drug and ethyl-ester formation products by GC/MS. Pharmacokinetic parameters were calculated for both in vitro and in vivo experiments. 2-Meperidine and 2-cocaethylene were formed from MEP and CE, respectively, in the presence of ²H₆-ethanol. The pharmacokinetics of meperidine and cocaethylene were significantly altered, increasing t1/2, when ethanol was given in combination with drug. Ethylphenidate (EPH) was formed both in vivo and in vitro when MPH and ethanol were administered. There was no significant change in MPH pharmacokinetics in the presence of ethanol both in vitro and in vivo. EPH administered to male Sprague-Dawley rats increased locomotor activity in equal intensity and duration to MPH. All ethanolic transesterification reactions investigated were completely inhibited by the addition of specific and non-specific carboxylesterase inhibitors in vitro, implicating a carboyl esterase-mediated transesterification process.Digitization note: p.184 missing from paper original