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Updated: Mar 7, 2026
Preparation and Characterization of Lipophilic Doxorubicin Pro-drug Micelles
Published on: August 2, 2016
A Model-Based Approach To Assessing the Importance of Intracellular Binding Sites in Doxorubicin Disposition
Ilse R Dubbelboer1, Elsa Lilienberg1, Erik Sjögren1
1Department of Pharmacy, Uppsala University , Box 580, 751 23 Uppsala, Sweden.
Abstract:
Doxorubicin is an anticancer agent, which binds reversibly to topoisomerase I and II, intercalates to DNA base pairs, and generates free radicals. Doxorubicin has a high tissue:plasma partition coefficient and high intracellular binding to the nucleus and other subcellular compartments. The metabolite doxorubicinol has an extensive tissue distribution. This porcine study investigated whether the traditional implementation of tissue binding, described by the tissue:plasma partition coefficient (Kp,t), could be used to appropriately analyze and/or simulate tissue doxorubicin and doxorubicinol concentrations in healthy pigs, when applying a physiologically based pharmacokinetic (PBPK) model approach, or whether intracellular binding is required in the semi-PBPK model. Two semi-PBPK models were developed and evaluated using doxorubicin and doxorubicinol concentrations in healthy pig blood, bile, and urine and kidney and liver tissues. In the generic semi-PBPK model, tissue binding was described using the conventional Kp,t approach. In the binding-specific semi-PBPK model, tissue binding was described using intracellular binding sites. The best semi-PBPK model was validated against a second data set of healthy pig blood and bile concentrations. Both models could be used for analysis and simulations of biliary and urinary excretion of doxorubicin and doxorubicinol and plasma doxorubicinol concentrations in pigs, but the binding-specific model was better at describing plasma doxorubicin concentrations. Porcine tissue concentrations were 400- to 1250-fold better captured by the binding-specific model. This model adequately predicted plasma doxorubicin concentration-time and biliary doxorubicin excretion profiles against the validation data set. The semi-PBPK models applied were similarly effective for analysis of plasma concentrations and biliary and urinary excretion of doxorubicin and doxorubicinol in healthy pigs. Inclusion of intracellular binding in the doxorubicin semi-PBPK models was important to accurately describe tissue concentrations during in vivo conditions.
Insights
This study shows that incorporating intracellular binding into pharmacokinetic models significantly improves the accuracy of predicting doxorubicin and doxorubicinol tissue concentrations in pigs. The binding-specific model better captures drug distribution compared to traditional methods.
Area of Science:
- Pharmacology
- Pharmacokinetics
- Toxicology
Background:
- Doxorubicin is a key anticancer drug with complex distribution due to high tissue binding and free radical generation.
- Understanding doxorubicin and its metabolite doxorubicinol tissue distribution is crucial for accurate pharmacokinetic modeling.
- Traditional models use tissue:plasma partition coefficients (Kp,t), but intracellular binding may be critical.
Purpose of the Study:
- To evaluate if traditional tissue binding parameters (Kp,t) are sufficient or if intracellular binding is necessary for accurate PBPK modeling of doxorubicin and doxorubicinol in pigs.
- To compare a generic semi-PBPK model using Kp,t with a binding-specific semi-PBPK model incorporating intracellular binding.
Main Methods:
- Two semi-PBPK models were developed for doxorubicin and doxorubicinol in pigs.
- Model 1: Generic model using conventional Kp,t for tissue binding.
- Model 2: Binding-specific model incorporating intracellular binding sites.
Main Results:
- Both models simulated biliary and urinary excretion and plasma doxorubicinol concentrations effectively.
- The binding-specific model demonstrated superior accuracy in describing plasma doxorubicin concentrations.
- Porcine tissue concentrations were 400- to 1250-fold better predicted by the binding-specific model.
Conclusions:
- Intracellular binding is essential for accurately modeling doxorubicin tissue concentrations in vivo.
- The binding-specific semi-PBPK model provides a more accurate representation of doxorubicin pharmacokinetics in pigs.
- This improved modeling enhances understanding of drug distribution and potential toxicity.
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