Paclitaxel Ciclosporin

PACLITAXEL CICLOSPORIN t plasma concentrations of these drugs, with risk of toxic effects Competitive inhibition of CYP3A4-mediated metabolism and P-gp transport of these drugs Watch for toxic effects of these drugs... 

Drugs that are known to be substrates of P-gp include antihistamines (e.g. terfenadine), digoxin, ciclosporin, hydrocortisone and other steroids and drugs used in chemotherapy (e.g. paclitaxel, vinblastine). Ciclosporin, in addition to being a substrate of P-gp, is also an inhibitor of P-gp. Drugs known to induce P-gp include morphine, dexamethasone, phenobarbital, rifampin and St John s wort. Inhibitors of P-gp include amiodarone, amitriptyline, atorvastatin, chlorpromazine, ciclosporin, erythromycin, fluphenazine, haloperidol, quinidine, ritonavir and verapamil,... 

There was a dramatic increase in the systemic availability of paclitaxel when ciclosporin was administered concomitantly (241) and in a phase I study of the pharmacokinetics of twice-daily oral paclitaxel 60-160 mg/m in 15 patients in combination with ciclosporin (15 mg/kg) there was a seven-fold increase in the systemic exposure to paclitaxel the plasma concentration increased from negligible to therapeutic concentrations (242). The inhibitory effect of ciclosporin on the gastrointestinal multidrug transporter P-glycoprotein was suggested to account for these interactions. 

Anaphylactoid reactions can occur after the intravenous administration of Cremophor (SEDA-22, 526) when it is used as a diluent of alfadolone/afaxolone (SED-11,211) (2), ciclosporin (3), paclitaxel (4), propanidid (SED-11, 211) (5,6), teniposide (7), and vitamin K (8,9). Cardiorespiratory arrest after intravenous miconazole has been attributed to the histamine-releasing properties of Cremophor (10). 

I. ANTIARRHYTHMICS - disopyramide, propafenone 2. ANTIBIOTICS-chloramphenicol, doxycycline, metronidazole, rifampicin, telithromycin 3. ANTICANCER AND IMMUNOMODULATING DRUGS - carmustine, ciclosporin, corticosteroids, doxorubicin, etoposide, ima-tinib, lomustine, paclitaxel, tacrolimus, tamoxifen, toremifene, vinca alkaloids... 

Ciclosporin increases the levels of docetaxel and paclitaxel after oral administration. 

Oral paclitaxel has poor bioavailability because of a high affinity for P-glycoprotein in the gastrointestinal tract. Studies in mice have shown that the combination of ciclosporin with oral paclitaxel produced a tenfold increase in systemic exposure to paclitaxel. Plasma levels of paclitaxel were below therapeutic concentrations in 5 patients when they were given an oral dose (intravenous formulation) of paclitaxel 60 mg/m followed by intravenous doses of 175 mg/m for subsequent courses. However, therapeutic levels above 100 micromol/mL (a ninefold increase) were achieved in 9 patients who received the same regimen with ciclosporin 15 mg/kg. The combination was well-tolerated, but further study is required to determine whether paclitaxel treatment via the oral route is as active as that by the intravenous route. ... 

Especially the inhibition or induction of cytochrome P450 subtype 3A4 (CYP 3A4) is clinically relevant, because a variety of active substances and food substances (e.g. grapefruit juice) are able to affect this enzyme. Substances inhibiting CYP 3A4 include ciclosporin, dihydropyridines, verapamil, midazolam, paclitaxel, simvastatin, lovastatin, atorvastatin, cimetidine, erythromycin, troleandomycin, ketoconazole (and other azoles). Substances inducing CYP 3A4 include steroids, rifampicin, phenobarbital and St John s wort. 

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