Laboratory of Experimental and Applied Pharmacokinetics and Pharmaco-omics (LEAP2)

Pharmacokinetic and pharmacodynamic considerations in development of new pharmaceutical products


Pharmacokinetics is defined as the quantification of drug and metabolite concentrations in the body as a function of time. The data are then presented in the formulation of equations, which characterize the process of drug absorption, distribution, metabolism and elimination (ADME).


Pharmacodynamics is often defined as quantifying the drug action as a function of the drug or metabolite concentration or an administered dose. It has been long recognized that the intensity and duration of the pharmacological effect of a systemically administered drug are functions not only of the intrinsic activity of the drug, but also of its absorption, distribution, metabolism and excretion characteristics.


One of the approaches utilizes human colon carcinoma cells, such as the Caco-2, HT-29, SW116, LS174T and SW-480 cell lines to investigate drug absorption. Up to date, Caco-2 cell line has been the most commonly used in vitro model. Caco-2 cells are comparable to small intestine absorptive cells in ion transport, vitamin uptake and general morphological characteristics. Although the Caco-2 cell model has the advantages of simplicity, reproducibility and rapid turnaround time, it has the following limitations:

  1. The villus in the small intestine contains more than one cell type.
  2. The Caco-2 cell line does not produce the mucus as observed in the small intestine.
  3. No P-450 metabolizing enzyme activity has been found in the Caco-2 cell line.


There is also limited information published on the correlation between oral drug absorption in humans and the apparent drug permeability coefficients obtained from the Caco-2 cell model. Therefore, the cell-based technologies could be used as early screens in drug discovery and development, but cannot be used to substitute the in vivo pharmacokinetic studies.


Our research group has been involved in the cell-based and also in vivo pharmacokinetic and pharmacodynamic studies of a number of pharmaceutical compounds, including anti-leukemic, immunosuppressive, and anti-cancer agents. We used vitamin A acid as one of the examples. Vitamin A acid is potent chemotherapeutic agent for the treatment of acute promyelocytic leukemia (APL). Its poor aqueous solubility not only affects its oral absorption, but also prevents it from forming an aqueous parenteral formulation. Under special circumstances (such as in comatose patients), it will be impossible to administer the capsule orally. Recently, we developed a water-soluble formulation of the vitamin A acid. Pharmacokinetic studies were carried after oral and intravenous administration. Results showed that the formulation could be administered intravenously. The water-based formulation was also found to greatly improve the oral absorption of the compound. The pharmacological activity of this formulation will also be tested in leukemic cell model. This example illustrates that a pharmaceutical product can be developed through a problem-solving approach with the use of pharmaceutics in formulation development and pharmacokinetics in its evaluation. These studies were carried out through inter-disciplinary collaborations with pharmaceutical scientist, pharmacologist and clinician.