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Dose-Response Relationship: Selectivity and Specificity01:25

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Drugs exert their therapeutic effects by interacting with receptors, enzymes, or ion channels that are present throughout the human body. The strength and duration of the interaction between a drug and its target receptor are characterized by the selectivity and specificity of the drug. Selectivity refers to a drug's strong preference for its intended target over other targets. For instance, isoprenaline, a non-selective β-adrenergic agonist, interacts with both β1- and...
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Agonists can bind with and activate receptors, resulting in the formation of drug-receptor complexes. Once formed, these complexes catalyze many biochemical processes at the cellular level and subsequently induce a pharmacologic response. The degree of response is directly proportional to the fraction of activated receptors, which in turn, depends on the concentration of the drug at the receptor site as well as the sensitivity of the receptor. An increase in the administered dose contributes to...
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Body tissues, comprising approximately 40% of the body weight, are crucial in drug distribution and localization. These tissues can serve as drug storage sites, competing with plasma binding sites for drug molecules.
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When toxic substances penetrate the human body, they disseminate to various tissues, undergoing metabolic changes. This process yields reactive metabolites that may covalently bind with specific target molecules, resulting in toxicity.
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The therapeutic index of a drug is a key parameter in pharmacology that quantifies the relative safety of a drug by calculating the ratio between the dose that causes toxicity in half the population (50%) to the dose that proves to be effective for half the population (50%). It provides a spectrum of doses for a particular drug ranging from effective to potentially toxic. To illustrate, consider an anticoagulant agent like warfarin. It possesses a narrow window within its therapeutic index to...
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Structure‒tissue exposure/selectivity relationship (STR) correlates with clinical efficacy/safety.

Wei Gao1, Hongxiang Hu1, Lipeng Dai1

  • 1Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.

Acta Pharmaceutica Sinica. B
|June 1, 2022
PubMed
Summary
This summary is machine-generated.

Drug optimization should consider structure-tissue exposure relationships (STR) alongside structure-activity relationships (SAR) to improve clinical efficacy and reduce toxicity. Balancing both optimizes drug candidate selection for better clinical development success.

Keywords:
Clinical efficacy/toxicityDrug developmentDrug optimizationStructure-tissue exposure/selectivity relationship (STR)Structure‒activity-relationship (SAR)

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Area of Science:

  • Pharmacology and Drug Development
  • Translational Medicine
  • Medicinal Chemistry

Background:

  • Current drug optimization focuses on structure-activity relationships (SAR) and drug-like properties.
  • This process may overlook structure-tissue exposure/selectivity relationships (STR), potentially impacting clinical efficacy and toxicity.
  • The balance between clinical efficacy and toxicity is crucial for successful drug development.

Purpose of the Study:

  • To investigate the correlation between structure-tissue exposure/selectivity relationships (STR) and clinical efficacy/toxicity.
  • To evaluate the impact of STR on drug candidate selection for clinical trials.
  • To determine if balancing SAR and STR improves drug development outcomes.

Main Methods:

  • Utilized seven selective estrogen receptor modulators (SERMs) with similar structures and molecular targets.
  • Analyzed the correlation between plasma exposure and tissue exposure (tumor, fat pad, bone, uterus).
  • Assessed the relationship between tissue exposure/selectivity and observed clinical efficacy/toxicity.

Main Results:

  • Drug plasma exposure did not correlate with exposure in target tissues.
  • Tissue exposure and selectivity of SERMs correlated significantly with clinical efficacy and safety.
  • Minor structural modifications altered tissue exposure/selectivity without changing plasma exposure.
  • High protein-bound SERMs accumulated more in tumors, potentially due to the enhanced permeability and retention (EPR) effect.

Conclusions:

  • Structure-tissue exposure/selectivity relationships (STR) significantly impact drug efficacy and toxicity in disease-targeted tissues versus normal tissues.
  • Drug optimization strategies must integrate both SAR and STR to enhance the selection of viable drug candidates.
  • Balancing SAR and STR is essential for improving the success rate of clinical drug development.