In Vivo Pharmacokinetic and Metabolism Services for Drug Development

Ricerca Biosciences, a partnered drug development organization, offers a wide range of services to the pharmaceutical industry. As well as designing in vitro and in vivo studies to identify your lead compound, we can provide a complete package of GLPcompliant studies to support your Phase I and II clinical studies. With an experienced synthetic chemistry team, we can also supply the radiolabeled drug substance required for these studies.

The study designs described below are intended as a guide only and can be tailored to suit individual requirements.

Pharmacokinetics Studies

The purpose of these studies is to establish the absolute bioavailability of the drug and to define pharmacokinetic parameters such as half-life, clearance and volume of distribution. Radiolabeled drug is administered both intravenously and by the intended clinical route, usually oral, to allow comparison of circulating levels of total drug-related material. With our extensive bioanalytical capability, parent compound and metabolites can be investigated 'cold' to complement toxicology/toxicokinetic studies.

Bioavailability in Rats

Rats are jugular vein cannulated to facilitate blood sampling. A single oral or intravenous dose is administered to groups of five males and five females. Typically, 8-10 blood samples are taken during the first 24 hours after dosing, followed by further samples at 24-hour intervals. Radioactive concentrations in blood and plasma are measured for seven days after dosing or until levels of radioactivity fall below the limit of detection. We recommend conducting an initial pilot study in the rat, using the oral route, to determine sampling times required to adequately define the plasma concentration-time curve.

Bioavailablility in Dogs

Dogs (three per sex) are dosed twice, once by intravenous injection and once orally, using a suitable washout period between doses. Samples are taken and analyzed in a similar manner to the rat study.

Excretion and Distribution Studies

The purpose of these studies is to assess the distribution of radiolabel in tissues over time, determine the routes and rate of excretion and the overall recovery of radioactivity following oral administration. Selected excreta samples are used to produce metabolite profiles for the toxicology species and these profiles are compared to those obtained in man.

Excretion Balance in Rats

Following oral administration of the radiolabeled drug, animals are placed in metabolism cages suitable for the separate collection of urine and feces. Excreta samples are collected for up to seven days following dose administration after which time the animals are killed and selected tissues are removed. The overall recovery of radioactivity is determined in excreta, tissues and residual carcass. Again we recommend conducting an initial pilot study in the rat to ensure an acceptable recovery of radioactivity and to check for the possibility of volatile metabolites being eliminated in expired air.

Excretion Balance in Dogs

Following oral administration of the radiolabeled drug, animals are placed in metabolism cages and urine and feces are collected for up to seven days. Since radioactivity is not generally determined in the carcass, it can be more cost-efficient to combine the excretion balance and pharmacokinetics studies in the dog.

Tissue Distribution in Rats

Animals are terminated at various times following oral administration of the radiolabeled drug. The time points are determined by the results of the rat pharmacokinetics study and typically include the absorption phase, time to maximum plasma concentrations (tmax), tmax plus one half-life, and the elimination phase. Concentrations of radioactivity are determined in blood and selected tissues.

Additional studies offered to answer specific questions:

• Biliary elimination and enterohepatic recirculation
• Metabolite isolation and identification
• Comparison of pharmacokinetic parameters for parent and identified metabolites in plasma using LC-MS(/MS)
• Fetal uptake in rats
• Milk transfer in rats
• Repeat dose pharmacokinetic and distribution studies
• ADME studies in other species
• ADME studies using alternative routes of administration