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The aim of this study was to evaluate the influence of CYP3A5 and ABCB1 gene polymorphisms on fentanyl pharmacokinetics and clinical responses in cancer patients undergoing conversion to a transdermal system. Sixty Japanese cancer patients being treated with a fentanyl transdermal reservoir system according to the current Japanese guidelines were enrolled. Blood samples were obtained 192 h after conversion to the fentanyl transdermal system. Clinical responses after fentanyl application were evaluated by determining the incidences of adverse effects and rescue medication. The plasma concentration of fentanyl normalized with the measured absorption rate was significantly higher in the CYP3A5*3/*3 group than in the *1/*1 and *1/*3 groups (p = 0.048 and 0.021, respectively). Greater incidences of central adverse effects were observed in CYP3A5*3/*3 patients than in *1/*1+*1/*3 patients (odds ratio [OR], 3.49; 95% confidence interval [95% CI], 1.13-10.75; p = 0.029). Fewer patients with the ABCB1 1236TT allele than the 1236C allele needed rescue medication (OR, 0.17; 95% CI, 0.03-0.89; p = 0.036). CYP3A5*3 affected the pharmacokinetics of fentanyl and increased the incidence of central adverse effects. ABCB1 1236TT was associated with decreased administration of rescue medication after switching to the transdermal fentanyl system. In conclusion, these gene polymorphisms may predict clinical responses to fentanyl in cancer patients being converted to the transdermal system.

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The pharmacokinetics of mycophenolic acid (MPA) and its glucuronide (mycophenolic acid phenolic glucuronide, MPAG) in lupus nephritis (LN) have not been fully characterized. The aim of this study was to evaluate the pharmacokinetics of MPA and MPAG in LN patients by comparing the pharmacokinetics with those of kidney transplant (KT) recipients. Six LN patients (World Health Organization class IV and V) and 24 KT recipients [8 recipients treated with tacrolimus (Tac) and 16 with cyclosporine (CyA)] during the early posttransplantation period were enrolled. Pharmacokinetic parameters of MPA and MPAG were compared between LN patients and Tac-treated or CyA-treated KT recipients. The area under the concentration-time curve (AUC0-12) of MPA normalized to mycophenolate mofetil (MMF) dose (mg/kg) was significantly lower in LN patients and CyA-treated KT recipients than in Tac-treated KT recipients [median (range), 2.19 (0.87-4.23), 2.36 (1.13-5.74), and 4.86 (3.25-6.75) microg x h/mL per mg/kg, P < 0.05 and P < 0.01, respectively]. Dose-normalized MPAG AUC0-12 was significantly lower in LN patients and slightly lower in Tac-treated KT recipients than in CyA-treated KT recipients [median (range), 35.0 (8.34-69.8), 51.6 (34.4-94.8), and 84.1 (34.7-152) microg x h/mL per mg/kg, P < 0.05 and P = 0.13, respectively]. The ratio of MPA AUC5-12 to AUC0-12, an estimate of MPA enterohepatic recirculation, was slightly higher in LN patients and Tac-treated KT recipients than in CyA-treated KT recipients [median (range), 0.44 (0.35-0.56), 0.45 (0.42-0.61), and 0.34 (0.22-0.55), P = 0.29 and P = 0.10, respectively]. Serum creatinine was significantly lower in LN patients than in Tac-treated and CyA-treated KT recipients. In conclusion, the pharmacokinetics of MPA in LN patients is characterized by high MPA clearance and in CyA-treated KT recipients. Despite this higher clearance of MPA, MPAG AUC0-12 was lower in LN patients most likely due to better renal function in LN patients.

Key words voriconazole; metabolite; nonlinear pharmacokinetics; N-oxidation; CYP2C19Voriconazole is a second-generation triazole antifungal agent. Compared with other azole antifungal agents, it has potent activity against a broader spectrum of clinically significant fungal pathogens, including Aspergillus, Candida, and some unusual organisms. 1) In clinical settings, voriconazole is initially administered for the treatment of invasive pulmonary aspergillosis and empirical antifungal therapy in patients with persistent fever and neutropenia and in non-neutropenic patients. 2,3) Therapeutic drug monitoring is recommended for voriconazole in order to ensure its safety and efficacy. An association between successful therapeutic outcome in fungal infections and plasma voriconazole concentrations has been reported. 4) The lowest effective concentration on trough of voriconazole was reported as 1-2 µg/mL. [4][5][6][7][8] In contrast, a higher plasma concentration on trough of voriconazole was associated with the incidence of adverse effects, such as ocular, neurological, or hepatic toxicity. These adverse effects were observed in patients whose plasma concentration on trough of voriconazole exceeded 4 µg/mL. 4,7,9,10) However, there is large interindividual variability in the plasma concentration on trough of voriconazole. The prediction of voriconazole concentration on trough remains extremely difficult in clinical settings.Voriconazole is available as intravenous and tablet formulations in Japan. The standard maintenance doses of voriconazole are 3 or 4 mg/kg for injection and 150, 200 or 300 mg twice daily for oral administration. Voriconazole exhibits a nonlinear pharmacokinetic profile at the clinical dose. 11) Voriconazole is metabolized mainly in the liver to the major metabolite voriconazole N-oxide (N-oxide). N-Oxide accounts for 72% of all circulating metabolites in the plasma. 12) Although vorizonazole N-oxide has minimal antifungal activity compared with voriconazole, it has been found to inhibit the metabolic activity of CYP3A4 and CYP2C19 in vitro. 12) Because voriconazole is mainly metabolized via CYP2C19 or CYP3A4, the N-oxide may have an effect on the metabolic profile of voriconazole. The determination of N-oxide together with voriconazole can be useful in evaluating the metabolic process of voriconazole.Several studies investigated factors related to the nonlinear pharmacokinetics of voriconazole. 11,13) The saturation of metabolic clearance is believed to cause nonlinear pharmacokinetics because voriconazole is eliminated predominantly by metabolism. However, there are no clinical reports on the relationship of voriconazole and its major N-oxide metabolite that take into consideration CYP2C19 gene variants. As previously described, CYP molecular species participate in the metabolism of voriconazole and CYP2C19 plays the most dominant role. The genetic variants of CYP2C19 exhibited a large interindividual variation in voriconazole exposure. [14][15][16] The genetic variants of CYP2C19 may affect the...