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Predicting Pharmacokinetic Properties of Potential Anticancer Agents via Their Chromatographic Behavior on Different Reversed Phase Materials.

ABSTRACT: The Quantitative Structure-Activity Relationship (QSAR) methodology was used to predict biological properties, i.e., the blood-brain distribution (log BB), fraction unbounded in the brain (fu,brain), water-skin permeation (log Kp), binding to human plasma proteins (log Ka,HSA), and intestinal permeability (Caco-2), for three classes of fused azaisocytosine-containing congeners that were considered and tested as promising drug candidates. The compounds were characterized by lipophilic, structural, and electronic descriptors, i.e., chromatographic retention, topological polar surface area, polarizability, and molecular weight. Different reversed-phase liquid chromatography techniques were used to determine the chromatographic lipophilicity of the compounds that were tested, i.e., micellar liquid chromatography (MLC) with the ODS-2 column and polyoxyethylene lauryl ether (Brij 35) as the effluent component, an immobilized artificial membrane (IAM) chromatography with phosphatidylcholine column (IAM.PC.DD2) and chromatography with end-capped octadecylsilyl (ODS) column using aqueous solutions of acetonitrile as the mobile phases. Using multiple linear regression, we derived the statistically significant quantitative structure-activity relationships. All these QSAR equations were validated and were found to be very good. The investigations highlight the significance and possibilities of liquid chromatographic techniques with three different reversed-phase materials and QSARs methods in predicting the pharmacokinetic properties of our important organic compounds and reducing unethical animal testing.

SUBMITTER: Janicka M

PROVIDER: S-EPMC8072580 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Predicting Pharmacokinetic Properties of Potential Anticancer Agents via Their Chromatographic Behavior on Different Reversed Phase Materials.

Janicka Małgorzata M Mycka Anna A Sztanke Małgorzata M Sztanke Krzysztof K

International journal of molecular sciences 20210420 8

The Quantitative Structure-Activity Relationship (QSAR) methodology was used to predict biological properties, i.e., the blood-brain distribution (log BB), fraction unbounded in the brain (fu,brain), water-skin permeation (log Kp), binding to human plasma proteins (log Ka,HSA), and intestinal permeability (Caco-2), for three classes of fused azaisocytosine-containing congeners that were considered and tested as promising drug candidate ...[more]

PMID: 33923942

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Project description:AimTo investigate the pharmacokinetics and disposition of simmitecan (L-P) that was a water-soluble ester prodrug of chimmitecan (L-2-Z) with potent anti-tumor activities in different experimental animals, and to assess its drug-drug interaction potential.MethodsSD rats were injected with a single iv bolus doses of L-P (3.75, 7.5 and 15 mg/kg). The pharmacokinetics, tissue distribution, excretion and metabolism of L-P and its active metabolite L-2-Z were studied through quantitative measurements and metabolite profiling with LC/MS. The binding of L-P and L-2-Z to rat plasma proteins was examined using an ultrafiltration method. Systemic exposures of beagle dogs to L-P as well as drug distribution in tumors of the nude mice xenograft model of human hepatic cancer SMMC-7721 cells were also examined. The metabolism of L-P by liver mcirosomal carboxylesterase in vitro was investigated in different species. The effects of L-P and L-2-Z on cytochrome P450 enzymes were examined using commercial screening kits.ResultsThe in vivo biotransformation of L-P to L-2-Z showed a significant species difference, with a mean elimination half-life t1/2 of approximately 1.4 h in rats and 1.9 h in dogs. The systemic exposure levels of L-P and L-2-Z were increased in a dose-dependent manner. In rats, approximately 66% of L-P and 79% of L-2-Z were bound to plasma proteins. In rats and the nude mice bearing human hepatic cancers, most organ tissues had significantly higher concentrations of L-P than the corresponding plasma levels. In the tumor tissues, the L-P levels were comparable to those of plasma, whereas the L-2-Z levels were lower than the L-P levels. In rats, L-P was eliminated mainly via biliary excretion, but metabolism played an important role in elimination of the intact L-P. Finally, L-P and L-2-Z exerted moderate inhibition on the activity of CYP3A4 in vitro.ConclusionL-P and L-2-Z have relatively short elimination half-lives and L-P is mainly eliminated via biliary excretion. The species difference in the conversion of L-P to L-2-Z and potential drug-drug interactions due to inhibition of CYP3A4 should be considered in further studies.

Dataset Information

Predicting Pharmacokinetic Properties of Potential Anticancer Agents via Their Chromatographic Behavior on Different Reversed Phase Materials.

Publications

Predicting Pharmacokinetic Properties of Potential Anticancer Agents via Their Chromatographic Behavior on Different Reversed Phase Materials.

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