Phenobarbital Ciclosporin

Inducers of UGT include carbamazepine, phenobarbital, phenytoin and rifampin. Inhibitors of UGTs include amitriptyline, chlorpromazine, ciclosporin, clomipramine, diazepam, lorazepam, nitrazepam and valproic acid,... 

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,... 

Serum ciclosiporin levels are markedly reduced by car-bamazepine, phenobarbital, or phenyiioin. The dosage of ciclosporin may need to be increased two- to fourfold to maintain adequate immunosuppression. Oxcarbazepine may cause a smaii decrease in ciclosporin leveis. Vaiproate appears not to affect ciclosporin levels but two case reports suggest that it may damage renal grafts and cause hepatotoxicity in patients taking ciclosporin. 

A threefold increase in ciclosporin clearance was seen in another child with a kidney transplant while taking phenobarbital. Reductions in ciclosporin levels due to phenobarbital have been described in other patients. " ... 

Another report describes an increase in ciclosporin levels from 512 to 810 nanograms/mL after phenytoin and phenobarbital were replaced by sodium valproate. ... 

In 5 cases an interacting antiepileptic was successfully replaced by sodium valproate, see Carbamazepine, Phenobarbital and Phenytoin, above.However, sodium valproate may not always be without problems because interstitial nephritis was suspected in one patient with a renal graft taking ciclosporin and valproate, and fatal valproate-induced hepatotoxicity occurred in another patient taking ciclosporin. ... 

It is thought that phenytoin, - carbamazepine and phenobarbital increase the metabolism of the ciclosporin by the liver (hepatic cytochrome P450 oxygenase system) thereby decreasing the serum levels. Oxcarbazepine produced only small reductions in ciclosporin levels, and the effect is probably due to weak induction of the cytochrome P450 isoenzyme CTT3A. Phenytoin also possibly reduces the absorption of the ciclosporin. ... 

None of these interactions is extensively documented but all appear to be established and of clinical importance. Serum ciclosporin levels should be well monitored if carbamazepine, phenobarbital or phenytoin are added and the ciclosporin dosage increased appropriately. Primidone is metabolised to phenobarbital by the liver, and therefore would be expected to reduce ciclosporin levels. Information about oxcarbazepine is very limited but small reductions in its dose, together with an increase in ciclosporin dose, may be adequate to control any interaction. However, more study is required before oxcarbazepine can be recommended as a suitable alternative. The effects of the interaction may persist for a week or more after the anticonvulsant is withdrawn. Sodium valproate seems not to alter ciclosporin levels, but the case reports of nephritis and hepatotoxicity suggest some caution is warranted. 

Nishioka T, Ikegami M, Imanishi M, Ishii T, Uemura T, Kunikata S, Kanda H, Matsuura T, Akiyama T, Kurita T. Interaction between phenobarbital and ciclosporin following renal transplantation a case report. Hinyokika Kiyo (1990) 36, 447-50. 

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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