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Determination of drug-like properties of a novel antileishmanial compound: In vitro absorption, distribution, metabolism, and excretion studies.

Mondal SK, Mondal NB, Banerjee S, Mazumder UK - Indian J Pharmacol (2009)

Bottom Line: The compound was found to be stable (>95% remaining) in all stability studies and aqueous solubility was 299.7 +/- 6.42 muM.The distribution coefficients (Log D) in octanol/PBS and cyclohexane/PBS systems were found to be 0.54 and -1.33, respectively.The methods were found to be very useful for day-to-day ADME studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Technology, Jadavpur University, India.

ABSTRACT

Unlabelled: In drug discovery research, the compounds should not only to be potent and selective but also must possess acceptable pharmacokinetic properties such as absorption, distribution, metabolism, and excretion (ADME) to increase success rate in clinical studies.

Objective: Exploration of drug-like properties of 2-(2-methylquinolin-4-ylamino)-N-phenyl acetamide, a potent antileishmanial compound by performing some in vitro ADME experiments along with validation of such studies.

Materials and methods: Experimental protocols were established and validated for stability (in PBS pH7.4, simulated gastric and intestinal fluid), solubility, permeability, distribution coefficient (Log D), plasma protein binding and metabolism by rat liver microsomes by using spectrophotometer or HPLC. Methods were considered valid if the results of the standard compounds matched with reported results or within acceptable range or with proper ranking (high-medium-low).

Results: The compound was found to be stable (>95% remaining) in all stability studies and aqueous solubility was 299.7 +/- 6.42 muM. The parallel artificial membrane permeability assay (PAMPA) indicated its medium permeability (Log Pe = -5.53 +/- 0.01). The distribution coefficients (Log D) in octanol/PBS and cyclohexane/PBS systems were found to be 0.54 and -1.33, respectively. The plasma protein binding study by the equilibrium dialysis method was observed to be 78.82 +/- 0.13% while metabolism by Phase-I enzymes for 1 hour at 37 degrees C revealed that 36.07 +/- 4.15% of the compound remained after metabolism.

Conclusion: The methods were found to be very useful for day-to-day ADME studies. All the studies with the antileishmanial compound ascertained that the compound bears optimum pharmacokinetic properties to be used orally as a potential drug for the treatment of leishmaniasis.

No MeSH data available.


Related in: MedlinePlus

Parallel artificial membrane permeability assay (A) Propranolol HCl; (B) Carbamazepine; (C) Warfarin; (D) Furosemide; (E) Methotrexate. Log Pe of S4 = −5.53 ± 0.01. Results are average of three experiments (n = 7) ± SEM
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Figure 0002: Parallel artificial membrane permeability assay (A) Propranolol HCl; (B) Carbamazepine; (C) Warfarin; (D) Furosemide; (E) Methotrexate. Log Pe of S4 = −5.53 ± 0.01. Results are average of three experiments (n = 7) ± SEM

Mentions: Solubility of S-4 was 299.70 μM in PBS pH 7.4 [Table 1]. Permeability results are summarized in Figure 2 where compounds of different permeability (high: Propranolol HCl, carbamazepine, medium: Warfarin, low: Furosemide, very low: Methotrexate) were compared with the reported results and S-4 showed medium permeability. It showed Log D values of 0.54 and −1.33 in the octanol /PBS system and in the cyclohexane/PBS system, respectively [Table 2]. Binding to the human plasma protein was 78.82% [Table 3]. Metabolism of different compounds is summarized in Table 4, and S-4 showed 36.07% compound remaining after metabolism.


Determination of drug-like properties of a novel antileishmanial compound: In vitro absorption, distribution, metabolism, and excretion studies.

Mondal SK, Mondal NB, Banerjee S, Mazumder UK - Indian J Pharmacol (2009)

Parallel artificial membrane permeability assay (A) Propranolol HCl; (B) Carbamazepine; (C) Warfarin; (D) Furosemide; (E) Methotrexate. Log Pe of S4 = −5.53 ± 0.01. Results are average of three experiments (n = 7) ± SEM
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2875737&req=5

Figure 0002: Parallel artificial membrane permeability assay (A) Propranolol HCl; (B) Carbamazepine; (C) Warfarin; (D) Furosemide; (E) Methotrexate. Log Pe of S4 = −5.53 ± 0.01. Results are average of three experiments (n = 7) ± SEM
Mentions: Solubility of S-4 was 299.70 μM in PBS pH 7.4 [Table 1]. Permeability results are summarized in Figure 2 where compounds of different permeability (high: Propranolol HCl, carbamazepine, medium: Warfarin, low: Furosemide, very low: Methotrexate) were compared with the reported results and S-4 showed medium permeability. It showed Log D values of 0.54 and −1.33 in the octanol /PBS system and in the cyclohexane/PBS system, respectively [Table 2]. Binding to the human plasma protein was 78.82% [Table 3]. Metabolism of different compounds is summarized in Table 4, and S-4 showed 36.07% compound remaining after metabolism.

Bottom Line: The compound was found to be stable (>95% remaining) in all stability studies and aqueous solubility was 299.7 +/- 6.42 muM.The distribution coefficients (Log D) in octanol/PBS and cyclohexane/PBS systems were found to be 0.54 and -1.33, respectively.The methods were found to be very useful for day-to-day ADME studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Technology, Jadavpur University, India.

ABSTRACT

Unlabelled: In drug discovery research, the compounds should not only to be potent and selective but also must possess acceptable pharmacokinetic properties such as absorption, distribution, metabolism, and excretion (ADME) to increase success rate in clinical studies.

Objective: Exploration of drug-like properties of 2-(2-methylquinolin-4-ylamino)-N-phenyl acetamide, a potent antileishmanial compound by performing some in vitro ADME experiments along with validation of such studies.

Materials and methods: Experimental protocols were established and validated for stability (in PBS pH7.4, simulated gastric and intestinal fluid), solubility, permeability, distribution coefficient (Log D), plasma protein binding and metabolism by rat liver microsomes by using spectrophotometer or HPLC. Methods were considered valid if the results of the standard compounds matched with reported results or within acceptable range or with proper ranking (high-medium-low).

Results: The compound was found to be stable (>95% remaining) in all stability studies and aqueous solubility was 299.7 +/- 6.42 muM. The parallel artificial membrane permeability assay (PAMPA) indicated its medium permeability (Log Pe = -5.53 +/- 0.01). The distribution coefficients (Log D) in octanol/PBS and cyclohexane/PBS systems were found to be 0.54 and -1.33, respectively. The plasma protein binding study by the equilibrium dialysis method was observed to be 78.82 +/- 0.13% while metabolism by Phase-I enzymes for 1 hour at 37 degrees C revealed that 36.07 +/- 4.15% of the compound remained after metabolism.

Conclusion: The methods were found to be very useful for day-to-day ADME studies. All the studies with the antileishmanial compound ascertained that the compound bears optimum pharmacokinetic properties to be used orally as a potential drug for the treatment of leishmaniasis.

No MeSH data available.


Related in: MedlinePlus