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Physicochemical properties determining drug detection in skin.

ABSTRACT: Chemicals, including some systemically administered xenobiotics and their biotransformations, can be detected noninvasively using skin swabs and untargeted metabolomics analysis. We sought to understand the principal drivers that determine whether a drug taken orally or systemically is likely to be observed on the epidermis by using a random forest classifier to predict which drugs would be detected on the skin. A variety of molecular descriptors describing calculated properties of drugs, such as measures of volume, electronegativity, bond energy, and electrotopology, were used to train the classifier. The mean area under the receiver operating characteristic curve was 0.71 for predicting drug detection on the epidermis, and the SHapley Additive exPlanations (SHAP) model interpretation technique was used to determine the most relevant molecular descriptors. Based on the analysis of 2561 US Food and Drug Administration (FDA)-approved drugs, we predict that therapeutic drug classes, such as nervous system drugs, are more likely to be detected on the skin. Detecting drugs and other chemicals noninvasively on the skin using untargeted metabolomics could be a useful clinical advancement in therapeutic drug monitoring, adherence, and health status.

SUBMITTER: Bittremieux W

PROVIDER: S-EPMC8932847 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Physicochemical properties determining drug detection in skin.

Bittremieux Wout W Advani Rohit S RS Jarmusch Alan K AK Aguirre Shaden S Lu Aileen A Dorrestein Pieter C PC Tsunoda Shirley M SM

Clinical and translational science 20211128 3

Chemicals, including some systemically administered xenobiotics and their biotransformations, can be detected noninvasively using skin swabs and untargeted metabolomics analysis. We sought to understand the principal drivers that determine whether a drug taken orally or systemically is likely to be observed on the epidermis by using a random forest classifier to predict which drugs would be detected on the skin. A variety of molecular descriptors describing calculated properties of drugs, such a ...[more]

PMID: 34793633

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Project description:In-situ forming implants (ISFIs) represent a simple, tunable, and biodegradable polymer-based platform for long-acting drug delivery. However, drugs with different physicochemical properties and physical states in the polymer-solvent system exhibit different drug release kinetics. Although a few limited studies have been performed attempting to elucidate these effects, a large, systematic study has not been performed until now. The purpose of this study was to characterize the in vitro drug release of 12 different small molecule drugs with differing logP and pKa values from ISFIs. Drug release was compared with polymer degradation as measured by lactic acid (LA) release and change in poly(DL-lactide-co-glycolide) (PLGA) molecular weight (MW) measured by size exclusion chromatography with multi-angle laser light scattering (SEC-MALS). Drug physical state and morphology were also measured using differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Together, these results demonstrated that hydrophilic drugs have higher burst release at 24 h (22.8-68.4%) and complete drug release within 60 days, while hydrophobic drugs have lower burst release at 24 h (1.8-18.9%) and can sustain drug release over 60-285 days. Overall, drug logP and drug physical state in the polymer-solvent system are the most important factors when predicting the drug release rate in an ISFI for small-molecule drugs. Hydrophilic drugs exhibit high initial burst and less sustained release due to their miscibility with the aqueous phase, while hydrophobic drugs have lower initial burst and more sustained release due to their affinity for the hydrophobic PLGA. Additionally, while hydrophilic drugs seem to accelerate the degradation of PLGA, hydrophobic drugs on the other hand seem to slow down the PLGA degradation process compared with placebo ISFIs. Furthermore, drugs that were in a crystalline state within the ISFI drugs exhibited more sustained release compared with amorphous drugs.

Dataset Information

Physicochemical properties determining drug detection in skin.

Publications

Physicochemical properties determining drug detection in skin.

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