Fluorouracil (5-FU) prodrug tegafur (FT) is used widely for treating cancer patients. It has been reported that CYP2A6 and thymidine phosphorylase (TP) are involved in the formation of 5-FU from FT. In this study, the relative contribution of cytochrome P450 (P450) to the formation of 5-FU from FT was assessed using human liver 9000 x g supernatant (S9) and hepatocytes, which contain both enzymes. Intrinsic clearances of 5-FU formation from FT by P450 (NADPH dependent) and TP (NADPH independent) in human liver S9 were 1.36 and 0.169 microL/min/mg protein, respectively. The formation of 5-FU from FT in human liver S9 was inhibited over 82% by 8-methoxypsoralen, a CYP2A6-selective inhibitor. The formation of 5-FU from FT was also evaluated in human hepatocytes, cells that not only exhibit P450 and TP activity but also have anabolic capacity. The results indicated that CYP2A6 played a major role in 5-FU formation, which was consistent with the results using human liver S9. Factors that can affect the level of CYP2A6 activity in patients, e.g., genetic polymorphism, should be considered when using FT for chemotherapy.
Olopatadine hydrochloride (CAS 140462-76-6, KW-4679, AL-4943A; hereinafter referred to as olopatadine) is a novel antiallergic drug that is a selective histamine H1 receptor antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. Olopatadine also inhibits the tachykininergic contractions in guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. Oral administration of olopatadine at doses of 0.03 mg/kg or higher reduces the symptoms of experimental allergic cutaneous responses and rhinoconjunctivitis in sensitized animals. Preclinical and clinical evaluations have demonstrated that olopatadine is a safe drug. After oral administration to healthy volunteers, olopatadine was rapidly and extensively absorbed. Unlike most other antiallergic drugs which are eliminated via hepatic metabolism, olopatadine is mainly excreted into urine. Olopatadine did not affect cytochrome P450 activities in human liver microsomes and consequently drug-drug metabolic interactions are unlikely. In double-masked clinical trials, olopatadine was shown to be effective at alleviating symptoms of allergic diseases. The drug (Allelock) was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, cutaneous pruritus, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000. An ophthalmic solution of olopatadine is also useful for the treatment of allergic conjunctivitis: this formulation (Patanol) was approved in the USA and the European Union for the treatment of seasonal and perennial allergic conjunctivitis in 1996 and 2002, respectively.
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