Association of decreased mRNA expression of multidrug and toxin extrusion protein 1 in peripheral blood cells with the development of flutamide-induced liver injury.

PURPOSE: The anti-prostate cancer drug flutamide occasionally causes hepatotoxicity, and predictive biomarkers of flutamide-induced liver injury (FILI) are needed to improve safety of this drug. The aim of this prospective study was to identify such a biomarker by analyzing peripheral blood samples from patients before flutamide therapy. METHODS: Blood samples were obtained from 52 patients with prostate cancer before flutamide therapy. FILI was defined as treatment-related elevation of the serum concentration of aspartate or alanine aminotransferase to more than twice the upper limit of the reference range. The patients were monitored for at least 6 months regarding FILI. Microarray and quantitative real-time PCR analyses were conducted to compare gene expression profiles between the groups with and without FILI. RESULTS: Seventeen patients developed FILI. Microarray analysis of the training set in 15 patients detected 11 annotated genes showing >twofold expression changes between the groups (p < 0.005). Quantitative PCR analysis of both the training set and validation set confirmed that mRNA levels of multidrug and toxin extrusion protein 1 (MATE1 or SLC47A1, encoded by 1 of the 11 genes) were significantly lower in patients with FILI. A small experiment on mice (three per group) showed that Mate1 knockout mice had an elevated serum concentration of 4-nitro-3-(trifluoromethyl)phenylamine, a major metabolite of flutamide, 2 h after administration of the drug, suggesting that Mate1 could affect the pharmacokinetics of flutamide. CONCLUSIONS: The MATE1 mRNA level in peripheral blood is a possible negative predictive biomarker of FILI.

The effect of carboxylesterase 1 (CES1) polymorphisms on the pharmacokinetics of oseltamivir in humans.

PURPOSE: The aim of this study was to examine whether carboxylesterase 1 (CES1A) genetic polymorphisms affect the pharmacokinetics of oseltamivir. METHODS: Thirty healthy Japanese male and female subjects ranging in age from 20 to 36 years voluntarily participated in this study. These subjects were administered a single 75-mg dose of oseltamivir (Tamiflu®), and blood samples were collected predose and up to 24 h after oseltamivir administration. Oseltamivir and its active metabolite, oseltamivir carboxylate, were measured by liquid chromatography-time of flight/mass spectrometry with solid-phase extraction. The CES1A diplotypes [a combination of haplotypes A (CES1A3-CES1A1), B (CES1A2-CES1A1), C (CES1A3-CES1A1variant), and D (CES1A2-CES1A1variant)] were determined by PCR-restriction fragment length polymorphism analysis and direct sequencing. RESULTS: All subjects completed the study according to the protocol, and no clinically meaningful adverse events were attributable to the administration of oseltamivir. No significant differences in the pharmacokinetic parameters of oseltamivir and oseltamivir carboxylate were observed according to CES1A genotype. In one subject, the peak concentration and area under the concentration-time curve (AUC) of oseltamivir were approximately tenfold higher than the mean values of the other subjects. CONCLUSIONS: In our study, the known interindividual variability in oseltamivir metabolism was not explained by CES1A genetic polymorphisms, but are likely the result of other factors. While one subject was found to exhibit an approximate tenfold higher AUC than the other subjects, no abnormal behaviors were associated with the increased oseltamivir plasma concentrations. Further studies are required to reveal the cause of individual differences in CES1A metabolism and the abnormal behavioral effects of oseltamivir.

Influence of dosing time on the efficacy and safety of finasteride in rats.

Finasteride (FIN), a widely used medication for the treatment of androgen-dependent diseases, blocks the conversion of testosterone to a more potent androgen, dihydrotestosterone (DHT). In this study, we investigated a dosing time-dependent effect and safety of FIN in rats. Androgen receptor (AR) mRNA and nuclear protein levels exhibited clear daily rhythms with the peak during the dark period in the prostate and during the light period in the liver. Repeated oral administration of FIN (5 or 100 mg/kg) at 3 h after lights on (HALO) for 2 weeks decreased serum DHT concentration throughout a 24-h period, whereas the dosing of the agent at 15 HALO decreased its level only transiently even in the higher dose group. FIN caused laboratory abnormalities in the 3 HALO group but not in the 15 HALO group. However, the effect of FIN on the prostate weight was not influenced by the dosing time. These results suggest that the safety, but not effect, of FIN depends on its dosing time in rats. The dosing of FIN in the active period might be a rational dosage regimen, which is needed to be confirmed in human subjects.

Chronopharmacology of angiotensin II-receptor blockers in stroke-prone spontaneously hypertensive rats.

Protective effect of valsartan (Val), an angiotensin II (AII)-receptor blocker (ARB), against organ damage is reported to depend on the dosing time in hypertensive patients. Dosing-time-dependent effect of Val on survival of stroke-prone spontaneously hypertensive rats (SHRSP) under a 12-h lighting cycle was examined. Val (4 mg/kg per day) and olmesartan medoxomil (OM) (1 mg/kg per day), another ARB with a slower dissociation from the AII receptor, were given once daily at 2, 8, 14, or 20 HALO (hours after lights on). Dosing-time-dependent differences in plasma drug concentrations and effect on blood pressure (BP) were also evaluated. Survival of SHRSP showed a dosing-time-dependent change during Val therapy, with a peak at 2 HALO and a trough at 14 HALO. OM equally prolonged survival in all groups. The BP-lowering effect persisted for more than 24 h after dosing of Val at 2 HALO and of OM at 2 and 14 HALO, but disappeared at 5.5-h after Val dosing at 14 HALO. Plasma concentrations of Val and OM were higher after dosing at 2 HALO than at 14 HALO. These results suggest that the chronopharmacological phenomenon of Val was partly due to the dosing-time-dependent difference in plasma concentration and subsequent duration of the antihypertensive effect. Slower dissociation of OM from AII receptors might have blunted a potential dosing-time-dependent event.

Chronopharmacology of Angiotensin II-receptor Blockers in Stroke-Prone Spontaneously Hypertensive Rats.

Protective effect of valsartan (Val), an angiotensin II (AII)-receptor blocker (ARB), against organ damage is reported to depend on the dosing time in hypertensive patients. Dosing-time-dependent effect of Val on survival of stroke-prone spontaneously hypertensive rats (SHRSP) under a 12-h lighting cycle was examined. Val (4 mg/kg per day) and olmesartan medoxomil (OM) (1 mg/kg per day), another ARB with a slower dissociation from the AII receptor, were given once daily at 2, 8, 14, or 20 HALO (hours after lights on). Dosing-time-dependent differences in plasma drug concentrations and effect on blood pressure (BP) were also evaluated. Survival of SHRSP showed a dosing-time-dependent change during Val therapy, with a peak at 2 HALO and a trough at 14 HALO. OM equally prolonged survival in all groups. The BP-lowering effect persisted for more than 24 h after dosing of Val at 2 HALO and of OM at 2 and 14 HALO, but disappeared at 5.5-h after Val dosing at 14 HALO. Plasma concentrations of Val and OM were higher after dosing at 2 HALO than at 14 HALO. These results suggest that the chronopharmacological phenomenon of Val was partly due to the dosing-time-dependent difference in plasma concentration and subsequent duration of the antihypertensive effect. Slower dissociation of OM from AII receptors might have blunted a potential dosing-time-dependent event.

A randomized clinical study of tea catechin inhalation effects on methicillin-resistant Staphylococcus aureus in disabled elderly patients.

OBJECTIVES: To evaluate the effects of tea catechin inhalation on methicillin-resistant Staphylococcus aureus (MRSA) in disabled elderly patients. DESIGN: Seven days, randomized, prospective study. SETTING: Three hospitals in Japan. PARTICIPANTS: Seventy-two patients aged 78 +/- 11 years (mean age +/- standard deviation) with cerebrovascular diseases, classified as disabled according to the activity of daily living and were either bedridden or required assistance for standing, and showing presence of MRSA in sputum. INTERVENTIONS: Inhalation of 2 mL tea catechin extract solution along with saline (3.7 mg/mL catechins, 43% of catechins are composed of epigallocatechin gallate), or saline alone, 3 times daily using a handheld nebulizer for 7 days. MEASUREMENTS: The endpoint of efficacy was the reduction rates of MRSA in sputum. The safety measure was the adverse events observed during the 7 days of inhalation. RESULTS: The reduction rates calculated as the summation of decrease and disappearance of MRSA in sputum at 7 days were 47% (17 of 36 patients) in the catechin group and 15% (5 of 33 patients) in the control group; the difference in the reduction rates between the 2 groups was statistically significant (P = .014). The disappearance rate of MRSA in sputum was higher in the catechin group (31%; 11 patients) when compared with the control group (12%; 4 patients), however the difference in the disappearance rate between the 2 groups was not statistically significant (P = .091). No adverse events, such as respiratory tract obstruction, allergic bronchial spasm, or skin eruption, including laboratory changes, were observed during the study. CONCLUSION: The catechin inhalation appeared to reduce the MRSA count in sputum. However, the application of tea catechin inhalation as a supplementary treatment for controlling MRSA infection remains controversial.

Population Pharmacokinetics of Digoxin in Duchenne Muscular Dystrophy (DMD) Patients.

Routine clinical pharmacokinetic data collected from Duchenne muscular dystrophy (DMD) patients receiving digoxin have been analyzed to evaluate the role of patients' characteristics for estimating dosing regimens. The data were analyzed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. The pharmacokinetic model of digoxin was described using a one-compartment steady-state model. The effect of factors on digoxin clearance was investigated. NONMEM estimates indicate that digoxin clearance was influenced by the variables of body weight and combination with diuretics. The interindividual variability in digoxin clearance was modeled with proportional error with an estimated coefficient of variation of 25%, and the intraindividual variability in digoxin concentration was modeled with equal error with an estimated standard deviation of 0.0828 ng ml(minus sign1). In order to determine whether the population parameters obtained in this study were accurate, we administered digoxin according to individual dosage regimens in four DMD patients, using these values obtained by the Bayesian method. As a result, we found that mean prediction error, which indicates the deviation of prediction accuracy for digoxin concentration in plasma, was small, as were mean absolute prediction error and root mean squared error, showing the accuracy of this prediction method. The dosing method based on clearance values obtained by NONMEM analysis allowed the prediction of the steady-state concentration as a function of maintenance dose with acceptable error for therapeutic drug monitoring.