In Vitro Enzyme Induction
Studies of in vitro enzyme induction are conducted in primary cultures of human hepatocytes. These studies provide information on clinically significant issues, such as:
- Pharmacokinetic tolerance
- Drug-drug interactions
- Increased elimination (auto-induction)
Our "gold standard" approach involves treating cultured hepatocytes from three human livers with the drug candidate and measuring microsomal enzyme activities, mRNA levels, immunoreactive protein levels and cell toxicity. We have strict selection criteria for the cultures used in our induction studies, ensuring the most reliable results.
STUDY DETAILS
ASSAY SELECTION
CYP1A2 Phenacetin O-deethylation
CYP2B6 Bupropion hydroxylation
CYP2C8 Amodiaquine N-dealkylation
CYP2C8 Paclitaxel 6α-hydroxylation
CYP2C9 Diclofenac 4´-hydroxylation
CYP2C19 S-Mephenytoin 4´-hydroxylation
CYP3A4/5 Testosterone 6β-hydroxylation
CYP3A4/5 Nifedipine oxidation
CYP3A4/5 Midazolam 1´-hydroxylation
TEST SYSTEM Primary human hepatocytes
Cell cultures in a multi-well format
Attaching cryopreserved hepatocytes
Immortalized human hepatocytes
CONTROLS Appropriate vehicle and positive controls (prototypical inducers) are included in the experiments based on the study design. Our experienced staff also ensures that the fold induction from study cultures agrees with known historical values for the prototypical inducers used.
AUTOMATION AND ANALYSIS - Tecan liquid-handling system
- Validated LC/MS/MS methods
- High-throughput Shimadzu autosamplers
- Deuterated internal standards
RELATED INFORMATION
FDA’s latest guidance document (PDF)
XenoTech Products: Hepatocytes
Informed Consent Statement
A single organization regulates and oversees the use of human tissue intended for transplantation in the United States, namely the United Network for Organ Sharing (UNOS). Organ donors may elect to have their organs used either for transplantation only, or for transplantation or research. Thus, the donor (or the donor's family) has the right to prevent the use of the donor's organs for research. Regardless of the use of donated organs, no compensation is given to the donor’s family; any such compensation is illegal in the United States. In those cases where donors (or family members) elect to withhold organs from research uses, any organs that cannot be transplanted are discarded.
XenoTech receives hepatic, renal, intestinal, pulmonary, and other human tissue from various regional organ procurement organizations (OPOs) that obtain organs approved for research use. Regulations in the United States require that, regardless whether the organ is intended for transplantation or research purposes, the organ donor's identity be treated as highly confidential information. Organ procurement organizations maintain the informed consent records from each donor, and our Standard Operating Procedure requires that XenoTech personnel confirm the existence of informed consent for research purposes, prior to transport of organs to XenoTech. This procedure is intended to ensure that XenoTech manufactures human-derived products only when informed consent has been granted for research use of those specific organs. XenoTech does not, and, in consideration of confidentiality, cannot obtain the informed consent records from these organizations.
All human tissue accepted by XenoTech has been tested for the possible presence of various infectious diseases, and XenoTech does not accept human-derived material unless the donor has tested negative (non-reactive) for RPR, HIVAb, HTLVAb, HBsAg and HCVAb. All human tissue is also tested for CMVAb. However, due to the widespread (nearly ubiquitous) appearance of CMV in the population, and its relative insignificance as an infectious agent, tissues from donors reactive for CMVAb are accepted. The serology status of each donor is typically determined by ELISA by the organ procurement hospital.
XenoTech does not deal directly with - nor does it make any direct payments to - the surgeons who procure organs or the medical institutions where they work.