27 MAY 2023

Pharmacokinetics (PK) is often referred to as “what the body does to a drug,” as the study of a drug’s absorption, distribution, metabolism, and excretion (ADME)¹. Alternatively, pharmacodynamics (PD) describes “what a drug does to the body,” by involving receptor binding, chemical interactions, and post-receptor effects². During the drug development process, it is vital to understand the interactions between the drug and the body. Therefore, it is essential to conduct PK and PD studies in animal models in the processes of drug evaluation, new drug design, and drug optimization.

Organ distribution studies investigate how the drug reaches its target location and accumulates in various tissues after delivery. The distribution pattern can be affected by both physical (such as degree of ionization, lipophilic/hydrophilic) and physiological (such as protein binding, tissue uptake, systemic and regional blood flow) processes³. Distribution is measured by a fundamental PK parameter, volume of distribution, which describes the amount of drug present in the tissues versus in the blood, and is important in determining half-life and dosing regimen⁴.

PDS offers in vivo distribution PK testing using ICR mice. Vehicle and test articles will be administered intravenously, intraperitoneally, orally, or subcutaneously per the sponsor’s request. At assigned time points post-dosing (determined by the sponsor), the animals are euthanized by CO₂ and the plasma and specific organ samples were collected. The plasma or organ samples are processed and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A plasma or organ calibration curve for each compound is generated. To generate a plasma or organ calibration curve for each compound, aliquots of drug-free plasma or organs are spiked with the test compound at the specified concentration levels. The spiked plasma samples are processed together with the unknown plasma or organ samples using the same procedure. The reportable linear range of the assay is determined, along with the lower limit of quantitation (LLOQ).

Plots of plasma and organ concentration of compounds (ng/mL or ng/g) versus time are constructed (semi-log plot). The fundamental pharmacokinetic parameters of compound after PO, IV, or SC (T_max, C_max, AUC_last, AUC_lnf, AUC/D, AUC_Extr and MRT), and IV (t_1/2, C₀, AUC_last, AUC_Inf, AUC_Extr, MRT, V_ss, and CL) are obtained from the non-compartmental analysis (NCA) of the plasma data using WinNonlin. The bioavailability (F) and the ratios of plasma: organ are also calculated.

We use levofloxacin as a reference article. The exposure levels (ng/mL) of levofloxacin in plasma (ng/mL) and the major organs (heart, liver, spleen, lung, kidney, and brain) over time after subcutaneous (SC) or intravenous (IV) administration are shown in Figure 1; also, the ratios of the exposure levels in plasma and major organs over time are shown in Table 1.

Figure 1. The exposure levels (ng/mL) of levofloxacin in plasma (ng/mL) and the major organs (heart, liver, spleen, lung, kidney, and brain) over time after subcutaneous (SC; 3 mg/kg) or intravenous (IV; 1 mg/kg) administration.

Table 1. Ratios of the exposure levels in plasma and major organs over time after subcutaneous (SC; 3 mg/kg) or intravenous (IV; 1 mg/kg) administration.

Subcutaneous (SC; 3 mg/kg) route

Intravenous (IV; 1 mg/kg) route

Our laboratory staff has an average of 15 years of experience in conducting in vivo pharmacology studies. We fully comply with the species-specific recommendations of the Guide for the Care and Use of Laboratory Animals (2011) for husbandry and animal handling, and conduct studies within the facility accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International).

Other Available Pharmacokinetics Studies

1. Ruiz-Garcia A, Bermejo M, Moss A, Casabo VG. Pharmacokinetics in drug discovery. J Pharm Sci. 2008 Feb;97(2):654-90.
2. Currie GM. Pharmacology, Part 1: Introduction to Pharmacology and Pharmacodynamics. J Nucl Med Technol. 2018 Jun;46(2):81-86.
3. van den Anker J, Reed MD, Allegaert K, Kearns GL. Developmental Changes in Pharmacokinetics and Pharmacodynamics. J Clin Pharmacol. 2018 Oct;58 Suppl 10:S10-S25.
4. Ward RM, Kern SE, Lugo RA. Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics. Avery’s Diseases of the Newborn, Ninth Edition. 2012; 417–428.
5. National Research Council of the National Academies (US), Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals. 8th ed. Washington, D.C.: National Academies Press (US); 2011.