Top Gene Interactions
- Metabolism: At the present time, the exact metabolic route and fate of thalidomide is not known in humans. Thalidomide itself does not appear to be hepatically metabolized to any large extent, but appears to undergo non-enzymatic hydrolysis in plasma to multiple metabolites. Thalidomide may be metabolized hepatically by enzymes of the cytochrome P450 enzyme system. The end product of metabolism, phthalic acid, is excreted as a glycine conjugate. In a repeat dose study in which THALOMID™ (thalidomide) 200 mg was administered to 10 healthy females for 18 days, thalidomide displayed similar pharmacokinetic profiles on the first and last day of dosing. This suggests that thalidomide does not induce or inhibit its own metabolism. Route of Elimination: Thalidomide itself has less than 0.7% of the dose excreted in the urine as unchanged drug. Half Life: The mean half-life of elimination ranges from approximately 5 to 7 hours following a single dose and is not altered upon multiple dosing.
- Uses/Sources: For the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). Also for use as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence. Used to treat multiple myeloma.
- Health Effects: The most serious toxicity associated with thalidomide is its documented human teratogenicity. The risk of severe birth defects, primarily phocomelia or death to the fetus, is extremely high during the critical period of pregnancy. The critical period is estimated, depending on the source of information, to range from 35 to 50 days after the last menstrual period. The risk of other potentially severe birth defects outside this critical period is unknown, but may be significant. Based on present knowledge, thalidomide must not be used at any time during pregnancy. Thalidomide can cause severe birth defects in humans.
- Symptoms: Thalidomide is associated with drowsiness/somnolence, peripheral neuropathy, dizziness/orthostatic hypotension, neutro-penia, and HIV viral load increase.
- Treatment: Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored. (L1721)
- Route of Exposure: The absolute bioavailability has not yet been characterized in human subjects due to its poor aqueous solubility. In studies of both healthy volunteers and subjects with Hansen’s disease, the mean time to peak plasma concentrations (Tmax) ranged from 2.9 to 5.7 hours indicating that thalidomide is slowly absorbed from the gastrointestinal tract.
- Carcinogenicity: No indication of carcinogenicity to humans (not listed by IARC).
- Toxicity: The R-configuration and the S-configuration are more toxic individually than the racemic mixture. The LD<sub>50</sub> could not be established in mice for racemic thalidomide, whereas LD<sub>50</sub> values for the R and S configurations are reported to be 0.4 to 0.7 g/kg and 0.5 to 1.5 g/kg, respectively.
Mechanism of Action
|Target Name||Mechanism of Action||References|
Prostaglandin G/H synthase 2
Tumor necrosis factor
Nuclear factor NF-kappa-B p105 subunit
|In patients with erythema nodosum leprosum (ENL) the mechanism of action is not fully understood. Available data from in vitro studies and preliminary clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-a) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. For example, administration of thalidomide has been reported to decrease circulating levels of TNF-a in patients with ENL, however, it has also been shown to increase plasma TNF-a levels in HIV-seropositive patients.||
Nuclear receptor subfamily 1 group I member 2
Hepatocyte nuclear factor 4-alpha
Fibroblast growth factor receptor 2
Nuclear factor kappa-light-chain-enhancer of activated B cells