Paclitaxel Protease inhibitors

Chemotherapy Cyclophosphamide, erlotlnlb, ifos-famide, paclitaxel, tamoxifen, vinblastine, vincristine HIV protease inhibitors Amprenavir, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir HMG-CoA reductase inhibitors Atorvastatin, lovastatin, simvastatin... 

PACLITAXEL ANTIVIRALS-PROTEASE INHIBITORS t risk of adverse effects of docetaxel and paditaxel Inhibition of CYP3A4-mediated metabolism. Also inhibition of P-gp efflux of vinblastine Use with caution. Additional monitoring required. Monitor FBC weekly... 

A4 Barbiturates, carbamazepine, corticosteroids, efavirenz, phenytoin, rifampin, troglitazone Antiarrhythmics, antidepressants, azole antifungals, benzc iazepines, calcium channel blockers, cyclosporine, delavirdine, doxorubicin, efavirenz, erythromycin, estrogens, HIV protease inhibitors, nefazodone, paclitaxel, proton pump inhibitors, HMG-CoA reductase inhibitors, rifabutin, rifampin, sildenafil, SSRIs, tamoxifen, trazodone, vinca anticancer agents... 

Inhibition of P-gp could significantly increase drug concentrations in the CNS. Additionally, P-gp is highly expressed in the apical membrane of epithelial cells in the small and large intestine, where it transports drugs out of the cells into the intestinal lumen, thus limiting the bioavailability of compounds such as paclitaxel and HIV protease inhibitors. 

Life-threatening haematological toxicities have been reported in a few patients taking protease inhibitors when given paclitaxel or docetaxel. Nelfinavir and ritonavir appear to inhibit the clearance of paclitaxel and are predicted to inhibit the metabolism of docetaxel by CYP3A4. 

Paclitaxel is metabolised by the cytochrome P450 enzymes CYP2C8 and CYP3A4. Docetaxel is metabolised by CYP3A4. Protease inhibitors such as ritonavir and indinavir are known to inhibit CYP3A4, which might result in increased taxane levels and toxicity. 

Evidence is limited, nevertheless the UK manufacturers advise that paclitaxel should be given to patients also receiving protease inhibitors with caution. The manufacturers of docetaxel also advise that it should be used with caution with drugs that inhibit CYP3A4, see Taxanes Docetaxel + Miscellaneous , below, which would include the protease inhibitors. 

For many plants, methyl jasmonate is a key elicitor, which initiates a series of response mechanisms to herbivores, like the synthesis of protease inhibitors and the increased formation of secondary metabolites (cf section 3.3- Jasmonoids). The effects were already well-known for tomato and tobacco plants, but also for Catharanthus and Cinchona seedlings and for soya beans. In the case of yew cells, this additive enabled to increase the paclitaxel production from 3 to 117 mg, and later to 295 mg per litre of fermentation broth. 

Perhaps the largest body of work regarding the application of the Amdt-Eistert homologation is in the chain-extension of a-amino acids. The produced P-amino acids are components of many biologically active natural products, including paclitaxel (Taxol ), HIV protease inhibitors and P-lactam antibiotics. ... 

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