Development and Characterization of a New Oral Antileishmanial Bis(pyridine-2-Carboxamidine) Drug Through Innovative Dissolution Testing in Biorelevant Media Combined with Pharmacokinetic Studies
<b>Background/Objectives</b>: Currently there are very few effective oral antileishmanial treatments. In this study we evaluated a new bis(pyridine-2-carboxamidine) antileishmanial drug (JNII40_base) and its hydrochloride salt (JNII40_HCl). <b>Methods</b>: The characterizatio...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-06-01
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| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/17/7/838 |
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| Summary: | <b>Background/Objectives</b>: Currently there are very few effective oral antileishmanial treatments. In this study we evaluated a new bis(pyridine-2-carboxamidine) antileishmanial drug (JNII40_base) and its hydrochloride salt (JNII40_HCl). <b>Methods</b>: The characterization studies performed allowed us to determine the crystallinity, hydration water, and presence of hydrogen bonds in these drugs. Different dissolution methods were employed to predict intestinal absorption. A high-performance liquid chromatography–mass spectrophotometry (HPLC-MS/MS) method was developed for the determination of JNII40 in plasma. <b>Results</b>: Pharmacokinetic studies in rats of JNII40_base at 100 and 20 mg/kg, and JNII40_HCl at 20 mg/kg, showed a non-linear pharmacokinetic at high doses. An innovative biorelevant medium of phosphate buffer pH 6.8 with polysorbate 80 at 0.6% (<i>w</i>/<i>v</i>) showed high concentration values for JNII40_base at 30 min, which predicts good intestinal absorption. These results were consistent with the bioavailability data, which exhibited a significant (<i>p</i> < 0.05) increase in maximum plasma concentration (C<sub>max</sub>) and a slight delay in time to maximum (T<sub>max</sub>) compared to JNII40_HCl. Furthermore, the sustained release of JNII40_base in this biorelevant media was related to high plasma concentration values at 24 h (C<sub>24h</sub>) observed in bioavailability studies. These plasma concentrations of JNII40_base were above the half-maximal inhibitory concentration (IC<sub>50</sub>) against promastigote and amastigote forms of <i>Leishmania donovani</i>, which is indicative of effectiveness and should reduce the occurrence of drug resistance during treatments. <b>Conclusions</b>: The bioavailability and pharmacokinetic data support the consideration of this drug for further in vivo studies as an oral antileishmanial treatment. |
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| ISSN: | 1999-4923 |