Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Reporter: Prabodh Kandala, PhD

Scientists are reporting another reason — besides possible liver damage, stomach bleeding and other side effects — to avoid drinking alcohol while taking certain medicines. Their report in ACS’ journal Molecular Pharmaceutics describes laboratory experiments in which alcohol made several medications up to three times more available to the body, effectively tripling the original dose.

Christel Bergström and colleagues explain that beverage alcohol, or ethanol, can cause an increase in the amount of non-prescription and prescription drugs that are “available” to the body after taking a specific dose. Alcohol can change how enzymes and other substances in the body interact with many of the 5,000 such medications on the market. Some of these medications don’t dissolve well in the gastrointestinal tract — especially in the stomach and intestines. The researchers sought to test whether ethanol made these drugs dissolve more easily. If so, this would make the drugs more available in the body, possibly intensifying their effects when combined with alcohol.

To find out, the scientists used a simulated environment of the small intestine to test how rapidly medications dissolved when alcohol was and was not present. Almost 60 percent of the 22 medications in their tests dissolved much faster in the presence of alcohol. In addition, they found that certain types of substances, such as those that were acidic, were more affected. Some common acidic drugs include warfarin, the anticoagulant; Tamoxifen, used to treat certain forms of cancer; and naproxen, which relieves pain and inflammation.

Abstract:

Ethanol intake can lead to an unexpected and possibly problematic increase in the bioavailability of druglike compounds. In this work we investigated the effect of ethanol on the apparent solubility and dissolution rate of poorly soluble compounds in simulated intestinal fluid representing a preprandial state. A series of 22 structurally diverse, poorly soluble compounds were measured for apparent solubility and intrinsic dissolution rate (37 °C) in phosphate buffer pH 6.5 (PhB_6.5) and fasted state simulated intestinal fluid (FaSSIF, pH 6.5) with and without ethanol at 5% v/v or 20% v/v. The obtained data were used to understand for which molecules ethanol results in an increased apparent solubility and, therefore, may increase the amount of drug absorbed. In FaSSIF_20%ethanol 59% of the compounds displayed >3-fold higher apparent solubility than in pure FaSSIF, whereas the effects of 5% ethanol on solubility, in most cases, were negligible. Acidic and neutral compounds were more solubilized by the addition of ethanol than by lecithin/taurocholate aggregates, whereas bases showed a more substance-specific response to the additives in the buffer. The stronger solubilizing capacity of ethanol as compared to the mixed lipid aggregates in FaSSIF was further identified through Spearman rank analyses, which showed a stronger relationship between FaSSIF_20%ethanol and PhB_{6.5,20%ethanol} (r_S of 0.97) than FaSSIF_20%ethanol and FaSSIF (r_S of 0.86). No relationships were found between solubility changes in media containing ethanol and single physicochemical properties, but multivariate data analysis showed that inclusion of ethanol significantly reduced the negative effect of compound lipophilicity on solubility. For this data set the higher concentration of ethanol gave a dose number (Do) <1 for 30% of the compounds that showed incomplete dissolution in FaSSIF. Significant differences were shown in the melting point, lipophilicity, and dose profiles between the compounds having a Do < 1 and Do > 1, with the latter having higher absolute values in all three parameters. In conclusion, this study showed that significant effects of ethanol on apparent solubility in the preprandial state can be expected for lipophilic compounds. The results herein indicate that acidic and neutral compounds are more sensitive to the addition of ethanol than to the mixed lipid aggregates present in the fasted intestine.

http://www.sciencedaily.com/releases/2012/07/120726153953.htm

http://pubs.acs.org/doi/abs/10.1021/mp2006467