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The In Vitro Effects of Pentamidine Isethionate on Coagulation and Fibrinolysis

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Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, LA 70125, USA
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Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA
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Author to whom correspondence should be addressed.
Molecules 2019, 24(11), 2146; https://doi.org/10.3390/molecules24112146
Received: 17 May 2019 / Revised: 30 May 2019 / Accepted: 30 May 2019 / Published: 6 June 2019
(This article belongs to the Section Medicinal Chemistry)
Pentamidine is bis-oxybenzamidine-based antiprotozoal drug. The parenteral use of pentamidine appears to affect the processes of blood coagulation and/or fibrinolysis resulting in rare but potentially life-threatening blood clot formation. Pentamidine was also found to cause disseminated intravascular coagulation syndrome. To investigate the potential underlying molecular mechanism(s) of pentamidine’s effects on coagulation and fibrinolysis, we studied its effects on clotting times in normal and deficient human plasmas. Using normal plasma, pentamidine isethionate doubled the activated partial thromboplastin time at 27.5 µM, doubled the prothrombin time at 45.7 µM, and weakly doubled the thrombin time at 158.17 µM. Using plasmas deficient of factors VIIa, IXa, XIa, or XIIa, the concentrations to double the activated partial thromboplastin time were similar to that obtained using normal plasma. Pentamidine also inhibited plasmin-mediated clot lysis with half-maximal inhibitory concentration (IC50) value of ~3.6 μM. Chromogenic substrate hydrolysis assays indicated that pentamidine inhibits factor Xa and plasmin with IC50 values of 10.4 µM and 8.4 µM, respectively. Interestingly, it did not significantly inhibit thrombin, factor XIa, factor XIIIa, neutrophil elastase, or chymotrypsin at the highest concentrations tested. Michaelis-Menten kinetics and molecular modeling studies revealed that pentamidine inhibits factor Xa and plasmin in a competitive fashion. Overall, this study provides quantitative mechanistic insights into the in vitro effects of pentamidine isethionate on coagulation and fibrinolysis via the disruption of the proteolytic activity of factor Xa and plasmin. View Full-Text
Keywords: pentamidine; factor Xa; plasmin; coagulation; fibrinolysis pentamidine; factor Xa; plasmin; coagulation; fibrinolysis
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MDPI and ACS Style

Al-Horani, R.A.; Clemons, D.; Mottamal, M. The In Vitro Effects of Pentamidine Isethionate on Coagulation and Fibrinolysis. Molecules 2019, 24, 2146.

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