Prediction of Biliary Excretion in Rats and Humans Using Molecular Weight and Quantitative Structure–Pharmacokinetic Relationships
Journal Title: The AAPS Journal - Year 2009, Vol 11, Issue 3
Abstract
The aims were (1) to evaluate the molecular weight (MW) dependence of biliary excretion and (2) to develop quantitative structure–pharmacokinetic relationships (QSPKR) to predict biliary clearance (CLb) and percentage of administered dose excreted in bile as parent drug (PDb) in rats and humans. CLb and PDb data were collected from the literature for rats and humans. Receiver operating characteristic curve analysis was utilized to determine whether a MW threshold exists for PDb. Stepwise multiple linear regression (MLR) was used to derive QSPKR models. The predictive performance of the models was evaluated by internal validation using the leave-one-out method and external test groups. A MW threshold of 400 Da was determined for PDb for anions in rats, while 475 Da was the cutoff for anions in humans. MW thresholds were not present for cations or cations/neutral compounds in either rats or humans. The QSPKR model for human CLb showed a significant correlation (R2 = 0.819) with good prediction performance (Q2 = 0.722). The model was further assessed using a test group, yielding a geometric mean fold-error of 2.68. QSPKR models with significant correlation and good predictability were also developed for CLb in rats and PDb data for anions or cation/neutral compounds in rats and humans. Both CLb and PDb data were further evaluated for subsets of MRP2 or P-glycoprotein substrates, and significant relationships were derived. QSPKR models were successfully developed for biliary excretion of non-congeneric compounds in rats and humans, providing a quantitative prediction of biliary clearance of compounds.
Authors and Affiliations
Xinning Yang, Yash A. Gandhi, David B. Duignan, Marilyn E. Morris
Keywords
Related Articles
- EP ID EP681486
- DOI 10.1208/s12248-009-9124-1
- Views 100
- Downloads 0
Microdialysis as a tool in local pharmacodynamics
In many cases the clinical outcome of therapy needs to be determined by the drug concentration in the tissue compartment in which the pharmacological effect occurs rather than in the plasma. Microdialysis is an in vivo t...
Poly(butylcyanoacrylate) and Poly(ε-caprolactone) Nanoparticles Loaded with 5-Fluorouracil Increase the Cytotoxic Effect of the Drug in Experimental Colon Cancer
The clinical use of 5-fluorouracil, one of the drugs of choice in colon cancer therapy, is limited by a nonuniform oral absorption, a short plasma half-life, and by the development of drug resistances by malignant cells....
The MDR1 C3435T polymorphism: Effects on P-glycoprotein expression/function and clinical significance
Challenges and Opportunities in Absorption, Distribution, Metabolism, and Excretion Studies of Therapeutic Biologics
With the advancement of biotechnology in the last two decades, optimized and novel modalities and platforms of biologic moieties have emerged rapidly in drug discovery pipelines. In addition, new technologies for deliver...
Inhalation Devices and Patient Interface: Human Factors
The development of any inhalation product that does not consider the patient needs will fail. The needs of the patients must be identified and aligned with engineering options and physical laws to achieve a robust and in...