A comparative study of the molecular structure, lipophilicity, solubility, acidity, absorption and polar surface area of coumarinic anticoagulants and direct thrombin inhibitors

Abstract

The methods of computational chemistry have been used to elucidate the molecular properties of coumarinic anticoagulants (acenocoumarol, phenprocoumon, warfarin and tecarfarin) and direct thrombin inhibitors (melagatran, dabigatran and their prodrug forms).

Enhanced Elimination of Dabigatran Through Extracorporeal Methods

“…Dabigatran is a highly polar compound that does not undergo oxidative metabolism and is primarily excreted unchanged in the urine [29,31]. The predominant route of dabigatran metabolism is conjugation to glucuronic acid [29], with UGT2B15 serving as the major enzyme for metabolism and UGT1A9 and UGT2B7 serving as minor contributors to this process [38].…”

“…Extracorporeal removal is a potential consideration for treatment in the setting of dabigatran toxicity. An evaluation of dabigatran's pharmacological profile suggests that extracorporeal removal can expedite its clearance from plasma (Table 2) [1,2,[28][29][30][31][32]. Several authors have provided evidence to support extracorporeal removal as a strategy to manage dabigatran-related hemorrhage [32][33][34].…”

Liquid chromatographic methods for the determination of direct oral anticoagulant drugs in biological samples: A critical review

“…Thus, as summarized in Annex 1, DOACs have a molecular weight that ranges between 435.88 and 627.73 g.mol -1 [18][19][20]. As expected, because it is a prodrug, dabigatran etexilate shows the highest molecular weight due to its ethyl group in the carboxylic acid and the hexyloxycarbonyl side chain in the amidine [20].…”

“…Regarding polar surface area (PSA), dabigatran and dabigatran etexilate showed the highest values (150.22 and 154.05 Å, respectively Annex 1), while rivaroxaban exhibited the lowest value (88.18 Å) which may, together with the lower molecular weight, justify its higher bioavailability (around 80%, Annex 2) [18][19][20]. Indeed, drug permeability through biological membranes, such as small intestine and blood-brain-barrier, decreases as PSA increases [22,23].…”

“…In these cases, the coefficient of distribution is a better descriptor, since it takes into account not only the intrinsic lipophilicity but also the extent of ionization [10]. Dabigatran presents a moderate lipophilicity when compared with its prodrug (Log P values of 2.17 and 5.17, respectively, Annex 1) [19]. The water solubility of DOACs ranges between 4.66 (dabigatran etexilate) and 97.47 mg L -1 (dabigatran), suggesting that, with the exception of dabigatran, all DOACs are slightly soluble in water but sufficiently lipophilic to be quickly absorbed [18][19][20].…”