In Vivo PK/TK Studies Services

We perform pharmacokinetic studies (all routes of administration including IP, IV, PO, SC etc.) in multiple species (rodent, dog, rabbit, guinea pig, monkey) for projects at the discovery screening stage (rapid turnaround to meet high-through-put needs), IND-enabling studies, as well as toxicokinetic studies. The data are interpreted by our Pharmacokinetics staff using industry-standard WinNonlin software.

  • All routes of administration in multiple species
    • IP, IV, IM, PO, SC, etc
    • Rodent, dog, rabbit, guinea pig, monkey
  • PK parameters
    • PO: AUC0-last, AUCinfinity, Cmax, Tmax, T1/2, MAT, MRTinfinity
    • IV: AUC0-last, AUCinfinity, Cmax,T1/2, CL, Vss, MAT, MRTinfinity
  • Surgical Models
    • Bile duct cannulation
    • Catheterization / access ports
    • Portal vein cannulation
  • In vivo PK profiling
    • dose proportionality
    • single dose vs. repeat dose

Blood Cell Partitioning

The blood–to-plasma concentration ratio of test article is determined in fresh mouse, rat, dog, monkey, and human blood. Percent blood cell distribution is calculated based on the blood and plasma concentrations and hematocrit. Analysis of samples is performed using LC/MS/MS methods.

Caco-2 cell permeability

Caco-2 cell permeability provides the data to predict absorption of drug candidates across the intestinal epithelial cell barrier. The drug absorption rates (Papp), recovery and its potential as a P-glycoprotein substrate or inhibitor are assessed.

Formulation Test

Absolute and relative bioavailability of test article is determined in mice, rats, dogs, and monkeys follow dose administration via various routes. Effect of stomach pH on oral absorption is determined in either dogs or monkeys.

In Vitro Metabolism

We provide a full range of in vitro and ex vivo assays utilizing microsomes, S9 fractions, or hepatocytes from multiple species, to study drug metabolism. Microsomal stability is commonly used as a discovery tool to predict the extent of hepatic first-pass metabolism. At later stages, it is important to minimize the potential of clinical drug-drug interactions between drug candidates and co-medications.

The CYP inhibition potential of new drug candidates can be assessed using a rapid, reliable, and specific CYP inhibition screening method WuXi Biology has developed. This method measures the activities of seven major human CYP isozymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) using selective substrates incubated with human liver microsomes and hepatocytes or using recombinant CYP isozymes and fluorescence method for high-through-put screening.

Services include:

  • In vitro metabolism
  • Metabolic stability and half-life determination
  • CYP450 isozyme inhibition
  • CYP450 isozyme phenotyping
  • Time-dependent inhibition
  • Reactive-intermediate trapping

Mass Balance

An excretion mass balance study can provide fundamental information about the rates and routes of elimination of a new drug candidate. Mass balance studies are often an important component of regulatory submissions.

We perform various mass balance studies in mice, rats, and dogs. Typically, a radiolabeled drug is administered intravenously and/or orally, and excretion of radioactivity is monitored in urine, feces, and occasionally bile.

In addition to providing information on the relative rates of excretion in urine and bile, these studies can indicate the percentage of an oral dose systemically absorbed.

Further information can be obtained by analyzing mass balance study samples for parent drug and individual metabolites using LC/flow scintillation detection or LC/MS/MS to find out routes of elimination of parent compound and its metabolites.

Metabolite Identification

Utilizing the strengths of bioanalysis, LC/MS/MS, and NMR for metabolite identification studies are routinely performed. The goal is to define metabolic pathways for new drug candidates. The studies are often performed in conjunction with mass balance excretion studies, using plasma, urine, or bile samples from mice, rats, dogs, monkeys, or humans. Metabolite identification studies can also be performed in vitro using liver microsomes, hepatocytes, or other preparations from humans or animal species.

Plasma Stability

In vitro plasma stability provides valuable information prior to in vivo PK testing. The samples containing test articles are incubated at 37 oC for different time. Analysis of plasma stability samples is performed using LC/MS/MS methods.

Protein Binding

Plasma protein binding can greatly influence the tissue distribution, clearance, and pharmacological effects of drugs. WuXi Biology performs discovery stage plasma protein binding assays, as well as more thorough studies for regulatory submissions and clinical samples, usually using equilibrium dialysis or ultrafiltration. Analysis of protein binding samples is typically performed using LC/MS/MS methods.

Solubility and Stability

Solubility of test article is determined in various single and mixed organic solvents and aqueous buffer at different pH. Stability in the solution is tested at different temperatures and in different storage periods. Concentration of test article in the solution is measured using a either validated or scientifically validated HPLC method.

SPF Animal Barrier Facility

The 6,000 f2 animal facility at HD Biosciences, a WuXi AppTec comapny, is specific pathogen free (SPF) and AAALAC-compliant facility. It contains 8 procedure rooms and 8 animal rooms which can house up to 2500 small animals. All the animal used for clients studies are provided by the certified animal supplier. All the study protocols and animal use are approved by the IACUC including a veterinarian on site.