temsirolimus

Ligand id: 5892

Name: temsirolimus

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Structure and Physico-chemical Properties

2D Structure
Calculated Physico-chemical Properties
Hydrogen bond acceptors 17
Hydrogen bond donors 4
Rotatable bonds 11
Topological polar surface area 241.96
Molecular weight 1029.6
XLogP 3.54
No. Lipinski's rules broken 2

Molecular properties generated using the CDK

No information available.
Summary of Clinical Use
Used in the treatment of renal cell carcinomas.
Mechanism Of Action and Pharmacodynamic Effects
Temsirolimus is a mTOR (controls cell division) kinase inhibitor that binds with high affinity to FK506 binding protein-12 (FKBP-12), thereby forming a drug/protein complex that inhibits the activation of mTOR, but at high concentrations (10-20 µM) can inhibit mTOR without binding FKBP-12. Inhibition of mTOR activity results in G1 growth arrest, and combined with concomittant reduction in levels of hypoxia-inducible factors HIF-1&alpha and HIF-2α and VEGF, results in a reduction in cell proliferation, angiogenesis, and glucose uptake and apoptosis.
Pharmacokinetics
Absorption/Distribution
Temsirolimus is administered as an intravenous infusion over 30-60 minutes and peak concentration is typically observed by the end of the infusion. Distribution is partitioned into formed blood elements, accounted for by the drug binding to FKBP-12 in blood cells.
Biotransformation/Metabolism
Temsirolimus is metabolized primarily in the liver by CYP3A4, generating sirolimus, the principal active metabolite found following IV treatment. It is recommended that the dose of everolimus should be reduced if a known CYP3A4 inhibitor is coadministered, or be increased if a CYP3A4 activator is coadministered.
Elimination
Temsirolimus is predominantly excreted in feces (76%) with 4.6% of drug and metabolites recovered in urine. 17% of drug was not recovered by either route following a 14-day sample collection.
Population pharmacokinetics
Temsirolimus and sirolimus pharmacokinetics are not significantly affected by age, gender or ethnicity in tested populations. In the pediatric population net exposure as measured by the sum of temsirolimus and sirolimus AUCs (AUCsum) was comparable to that for adults.
Organ function impairment
Since temsirolimus is cleared predominantly by the liver caution should be used when treating patients with hepatic impairment.
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