Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDIKGL2I0T)
  Drug Name Sorafenib Drug Info Paclitaxel (protein-bound) Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Antineoplastics Antineoplastics/Mitotic Inhibitors
  Structure

 Mechanism of Sorafenib-Paclitaxel (protein-bound) Interaction (Severity Level: Moderate)
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Sorafenib Paclitaxel (protein-bound)
      Mechanism CYP450 2C8 inhibitor CYP450 2C8 substrate
      Key Mechanism Factor 1
Factor Name Cytochrome P450 2C8
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Structure Sequence
MEPFVVLVLCLSFMLLFSLWRQSCRRRKLPPGPTPLPIIGNMLQIDVKDICKSFTNFSKVYGPVFTVYFGMNPIVVFHGYEAVKEALIDNGEEFSGRGNSPISQRITKGLGIISSNGKRWKEIRRFSLTTLRNFGMGKRSIEDRVQEEAHCLVEELRKTKASPCDPTFILGCAPCNVICSVVFQKRFDYKDQNFLTLMKRFNENFRILNSPWIQVCNNFPLLIDCFPGTHNKVLKNVALTRSYIREKVKEHQASLDVNNPRDFIDCFLIKMEQEKDNQKSEFNIENLVGTVADLFVAGTETTSTTLRYGLLLLLKHPEVTAKVQEEIDHVIGRHRSPCMQDRSHMPYTDAVVHEIQRYSDLVPTGVPHAVTTDTKFRNYLIPKGTTIMALLTSVLHDDKEFPNPNIFDPGHFLDKNGNFKKSDYFMPFSAGKRICAGEGLARMELFLFLTTILQNFNLKSVDDLKNLNTTAVTKGIVSLPPSYQICFIPV
Gene Name CYP2C8
Uniprot ID CP2C8_HUMAN
KEGG Pathway hsa:1558
Protein Family Cytochrome P450 family
Protein Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:7574697, PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:7574697, PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:7574697, PubMed:15766564, PubMed:19965576). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316).
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      Mechanism Description
  • Decreased metabolism of Paclitaxel (protein-bound) caused by Sorafenib mediated inhibition of CYP450 enzyme

Recommended Action
      Management Caution is advised during the concomitant use of paclitaxel and sorafenib. Close monitoring for toxicities of paclitaxel (e.g., bone marrow suppression, especially neutropenia conduction abnormalities peripheral neuropathy) and sorafenib (e.g., rash/desquamation hand-foot skin reaction hypertension hemorrhage cardiac ischemia myocardial infarction QT prolongation diarrhea anorexia gastrointestinal perforation wound healing complications) is recommended, and the dosage of each drug adjusted as necessary. No dosage adjustment should be needed when paclitaxel is coadministered with sorafenib following a 3-day break in sorafenib dosing.

References
1 Flaherty KT, Schiller J, Schuchter, et al "A phrase I trial of the oral, multikinase inhibitor sorafenib in combination with carboplatin and paclitaxel." Clin Cancer Res 14 (2008): 4836-42. [PMID: 18676756]
2 Okamoto I, Miyazaki M, Morinaga R, et al "Phase I clinical and pharmacokinetic study of sorafenib in combination with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer." Invest New Drugs 28 (2010): 844-53. [PMID: 19760364]
3 Product Information. Nexavar (sorafenib). Bayer Pharmaceutical Inc, West Haven, CT.