Changes in estimated glomerular filtration rate in patients administered proton pump inhibitors: a single-center cohort study.

Proton pump inhibitor (PPI) use may be associated with renal dysfunction. Renal dysfunction in PPI users requires evaluation of development and progression risks simultaneously, using estimated glomerular filtration rate (eGFR) slope, which indicates changes in eGFR per year. To the best of our knowledge, no studies have evaluated eGFR slope in PPI users. This study investigated the association between PPI use and renal dysfunction using eGFR slope. A single-center cohort study was conducted using the health records data at Hamamatsu University Hospital in Japan. Participants were defined as first users of acid-suppressing drugs (PPIs or Histamine H2 receptor antagonists (H2RAs)) from 2010 to 2021 and continuously prescribed for ≥ 90 days. The H2RA group was used for the propensity-score matching (PSM) to the PPI group to minimize the effects of confounders. The eGFR slope was estimated using a linear mixed effects model. Participants were stratified by baseline eGFR and age, respectively, as subgroup analyses. A total of 4,649 acid-suppressing drug users met the inclusion criteria, including 950 taking H2RAs and 3,699 PPIs. After PSM, 911 patients were assigned to each group. The eGFR slopes of the PPI and H2RA users were -4.75 (95% CI: -6.29, -3.20) and -3.40 (-4.38, -2.42), respectively. The difference between the groups was not significant. Significant declines in eGFR were observed with PPIs with baseline eGFR ≥ 90 and age < 65. PPI use for ≥ 90 days may hasten eGFR decline compared to H2RA use, especially in patients with eGFR ≥ 90 or age < 65.

Long-term efficacies of selective vasodilators in pulmonary arterial hypertension: a comprehensive comparison using a spontaneous reporting database.

There is no clinical evidence of differences in drugs associated with long-term survival in patients with pulmonary arterial hypertension (PAH) due to the small population and lack of information on death in Japanese medical database systems. This study evaluated whether patient data from a spontaneous reporting database could be used for comparing the effects of pulmonary vasodilators on long-term survival in PAH patients. PAH patient data reported in the Japanese Adverse Drug Event Report (JADER) database from April 2004 to July 2022 were extracted. Kaplan-Meier curves were used to compare survival times. Adjusted hazard ratios (aHRs) for all-cause mortality were determined using Cox proportional hazards models. Of 1969 PAH patients reported in the JADER database, 1208 were included in the survival analyses. The patient demographics were similar to those of the PAH population reported in the Japan Pulmonary Hypertension Registry. Among drugs targeting the prostacyclin pathway, epoprostenol was most associated with long-term survival (aHR, 0.38; 95% confidence interval (CI), 0.23-0.64). The PAH patients treated with endothelin receptor antagonists had improved survival, especially among the macitentan users (aHR, 0.30; 95% CI, 0.22-0.42). Sildenafil was associated with a poor prognosis in the PAH patients (aHR, 1.56; 95% CI, 1.19-2.04). Although our results must be interpreted with caution due to several limitations inherent to spontaneous reporting databases, our approach using the JADER database for survival analysis may provide useful information in limited situations such as the treatment of rare diseases including PAH.

Characterization of plasma daptomycin in patients with serum highly glycated albumin and obesity.

PURPOSE: Plasma daptomycin has not been fully characterized in diabetic and obese patients. This study aimed to evaluate the associations of plasma daptomycin with glycation of serum albumin and obesity. METHODS: Infectious patients (n = 70) receiving intravenous daptomycin were enrolled. The plasma concentration of total and free daptomycin were determined using liquid chromatograph-tandem mass spectrometer. The associations of the plasma concentrations of daptomycin with clinical factors including serum albumin fractionations and physical status (obese including overweight, body mass index ≥ 25.0) were investigated. Daptomycin doses were adjusted using total body-weight. RESULTS: The serum albumin level was positively and negatively correlated with the plasma concentration of total daptomycin and its free fraction proportion, respectively. The serum non-glycated albumin was negatively correlated with the free fraction proportion. The dose-normalized plasma concentration of total daptomycin was higher in the obese patients than in non-obese patients when the body-weight was corrected with total and adjusted values. For the dose adjustment with lean body-weight, no difference was observed in the dose-normalized plasma concentration of total daptomycin between the physical statuses. For each body-weight correction method, physical status did not affect the dose-normalized plasma concentration of free daptomycin. CONCLUSION: The glycation of serum albumin and obesity did not associate with dose-normalized plasma free daptomycin. In obese patients, daptomycin dosage adjustment with total body-weight and adjusted body-weight may lead to an apparent excessive exposure resulting in overdosage compared to lean body-weight.

Bleeding events among patients concomitantly treated with direct oral anticoagulants and macrolide or fluoroquinolone antibiotics.

Fluoroquinolones and macrolides may, due to a potential drug-drug interaction, increase the concentration of any concomitantly administered direct oral anticoagulant (DOAC) and thereby increase the risk of severe bleeding. However, clinical evidence for such an effect is scarce. The present study aimed to evaluate the association between the use of fluoroquinolones or macrolides and bleeding events in patients with concomitant DOAC use. This was a nationwide cohort study including 19 288 users of DOACs in 2008-2018 using information from Swedish national health registers. We compared the incidence of bleeding events associated with use of fluoroquinolones or macrolides using doxycycline as a negative control. Cox regression was used to calculate crude and adjusted hazard ratios (aHRs) in time windows of various length of follow-up after the start of antibiotic use. The incidence rates for fluoroquinolones and macrolides ranged from 12 to 24 and from 12 to 53 bleeding events per 100 000 patients in the investigated time windows. The aHRs (95% confidence interval) for use of fluoroquinolones and macrolides were 1.29 (0.69-2.44) and 2.60 (0.74-9.08) at the concomitant window, 1.31 (0.84-2.03) and 1.79 (0.75-4.29) at 30 days, and 1.34 (0.99-1.82) and 1.28 (0.62-2.65) at 150 days, respectively. With regard to fluoroquinolones, the present study suggests that the risk of bleeding when combined with DOACs, if any, is small. Codispensation of macrolides in patients on DOACs was not associated with an increased risk of bleeding. However, due to the small number of macrolide users, the results must be interpreted with caution.

Incidence of acute kidney injury after teicoplanin- or vancomycin- and piperacillin/tazobactam combination therapy: A comparative study using propensity score matching analysis.

INTRODUCTION: Combination therapy with vancomycin (VCM) and piperacillin/tazobactam (PIPC/TAZ) increases the risk of acute kidney injury (AKI). Teicoplanin (TEIC) has a lower risk of AKI than VCM. Currently, the difference in AKI risk after TEIC-PIPC/TAZ combination therapy and VCM-PIPC/TAZ combination therapy is controversial. This study aimed to compare AKI incidence after treatment with these two drug combinations using propensity score matching analysis. METHODS: This single-center cohort study used data extracted from patients' medical records. We included patients who received TEIC-PIPC/TAZ therapy (TEIC group) or VCM-PIPC/TAZ therapy (VCM group). After propensity score matching, AKI incidence, AKI stage, 30-day mortality, and time to AKI incidence were compared between the groups. RESULTS: After propensity score matching, 94 patients were matched in each group. AKI incidence was significantly lower in the TEIC group than in the VCM group (10.6% vs. 23.4%, odds ratio [95% confidence interval]: 0.39 [0.17-0.88], p = 0.03). AKI stage, 30-day mortality, and time to AKI incidence were not significantly different between the groups. CONCLUSIONS: This study suggested that AKI incidence may be lower in patients undergoing combination therapy with TEIC-PIPC/TAZ than in those receiving therapy with VCM-PIPC/TAZ. To prevent the occurrence of AKI, clinicians may need to choose TEIC instead of VCM for patients receiving PIPC/TAZ.

Association Between the Prothrombin Time-International Normalized Ratio and Concomitant Use of Antibiotics in Warfarin Users: Focus on Type of Antibiotic and Susceptibility of Bacteroides fragilis to Antibiotics.

BACKGROUND: The difference in type of antibiotics and susceptibility of Bacteroides fragilis to antibiotics may influence warfarin anticoagulation. However, these influences have not been clarified in clinical settings. OBJECTIVES: This study aimed to investigate association the between the prothrombin time-international normalized ratio (PT-INR) and concomitant use of antibiotics in a real-world population of warfarin users. METHODS: This was a single-center cohort study using data from health records and included patients who received ß-lactams (BLs)/fluoroquinolones (FQs) during ongoing warfarin treatment (2011-2015) at Hamamatsu University Hospital in Japan. Antibiotics were categorized into those to which B fragilis is susceptible (BLsus, FQsus) and those to which it is not (BLnon, FQnon) and into those given orally (BLpo, FQpo) or intravenously (BLiv, FQiv). Outcomes were excessive PT-INR and changes in PT-INR, defined as the ratio (INR ratio) and difference (ΔINR) of maximum PT-INR and baseline PT-INR. Excessive PT-INR was graded as INR ratio of >1.5 or >2.5. RESULTS: A total of 1185 warfarin users were included. The proportion of INR ratio >2.5 in FQiv was higher than in BLiv (95% CI: 1.59-46.5). The proportions with an INR ratio of >1.5 in BLsus and FQsus were higher than in BLnon (1.72-14.1) and FQnon (1.05-9.36), respectively. ΔINR values in FQpo, FQiv, and FQsus were higher than those in BLpo, BLiv, and FQnon, respectively. CONCLUSIONS AND RELEVANCE: Concomitant use of FQs, or of antibiotics to which B fragilis is susceptible is associated with higher risk of excessive anticoagulation. These findings would contribute to safe and proper antibiotic treatment in warfarin users.

Impact of Cachexia and Opioid Analgesic Cotreatment on Pregabalin Pharmacokinetics and Central Nervous System Symptoms in Cancer Patients.

BACKGROUND: Patients with cancer receiving pregabalin potentially have a high incidence of central nervous system (CNS) symptoms. The purpose of this study was to explore clinical factors influencing the incidence of CNS symptoms, including plasma pregabalin exposure, cancer cachexia, and opioid analgesic cotreatment. METHODS: Sixty-eight patients with cancer receiving twice-daily pregabalin were enrolled. Plasma concentrations of pregabalin, clinical laboratory data, opioid analgesic cotreatment, and the Glasgow Prognostic Score, which is an inflammation-based cachexia score, were considered as clinical factors. The incidence of CNS symptoms was collected from the patients' medical records. The predose plasma concentrations of pregabalin at steady state were determined by ultra-high-performance liquid chromatography. RESULTS: The steady-state trough plasma pregabalin concentrations showed a large variability with an interquartile range of 0.43-1.2 mg/L per mg/kg and were negatively correlated with an estimated glomerular filtration rate (eGFR). C-reactive protein (standardized partial regression coefficient, ß = 0.31) and opioid analgesic cotreatment (ß = 0.24) were also identified in addition to eGFR (ß = -0.60) in the multiple regression analysis. The incidence of CNS symptoms was significantly increased with opioid analgesic cotreatment and a higher Glasgow Prognostic Score but not with the absolute value of plasma pregabalin concentrations, eGFR, or other clinical laboratory data. CONCLUSIONS: In patients with cancer, steady-state trough plasma pregabalin concentrations were altered with renal function, systemic inflammation, and opioid analgesic cotreatment. However, a higher incidence of CNS symptoms observed in patients with cancer on pregabalin was more related to cachexia and opioid analgesic cotreatment than to altered pregabalin concentrations.

Airborne Monoterpenes Emitted from a Cupressus lusitanica Cell Culture Induce a Signaling Cascade that Produces ß-Thujaplicin.

A cell culture of Cupressus lusitanica was used to investigate the reaction of a plant to certain airborne chemicals. Compared with laboratory and field methods using intact plants or tissues, a cell culture is advantageous because it is not affected by environmental factors, and the experiments are easier to reproduce. When exposed to an elicitor, our cell line produces 10 monoterpenes and ß-thujaplicin, which is a strong phytoalexin. These monoterpenes are emitted into the vapor phase and are expected to play a role in airborne signaling. In the present study, the cells were exposed to monoterpene vapors, and the volatiles present in the culture flasks were monitored. When the culture cells were exposed to low doses of sabinene, we detected γ-terpinene and p-cymene. After exposure to γ-terpinene, we found p-cymene and terpinolene, whereas p-cymene exposure resulted in terpinolene emission. By contrast, the other seven monoterpenes we investigated did not induce any emissions of other monoterpenes. These results strongly suggest that in C. lusitanica a signaling cascade exists that starts with the emission of sabinene and moves to γ-terpinene, p-cymene, and finally to terpinolene, which accelerates the production of the phytoalexin ß-thujaplicin.

A Validated Fluorometric Method for the Rapid Determination of Pregabalin in Human Plasma Applied to Patients With Pain.

BACKGROUND: Pregabalin has been used for the treatment of pain. A clinically accepted method applied to patients with pain has not been published for the determination of pregabalin in human plasma. This study developed a fluorometric ultrahigh-performance liquid chromatography (UHPLC) method to measure pregabalin concentration in patients with pain. METHODS: After plasma pretreatment involving protein precipitation, pregabalin and gabapentin as an internal standard were derivatized with 4-fluoro-7-nitrobenzofurazan (NBD-F) under the following reaction conditions: 1 minute, pH 10, and 60°C. The UHPLC separation was performed using a 2.3-µm particle size octadecylsilyl column. The fluorescence detector was set at excitation and emission wavelengths of 470 and 530 nm, respectively. The predose blood samples were collected from 40 patients with pain who have been treated with 75 mg of pregabalin twice daily. RESULTS: The chromatographic run time was 1.25 minutes. No interfering peaks were observed in the blank plasma at the retention times of NBD derivatives. The calibration curve of pregabalin was linear at a range of 0.05-10 mcg/mL (r > 0.999). The lower limit of quantification was 0.05 mcg/mL. The intra-assay accuracy and precision were 98.3%-99.8% and within 4.3%, respectively. The inter-assay accuracy and precision were 103.2%-107.1% and within 4.1%, respectively. The predose plasma concentration of pregabalin in patients with pain ranged from 0.14 to 8.5 mcg/mL. CONCLUSIONS: This study provides a validated fluorometric UHPLC method with fast analytical performance for the determination of pregabalin in human plasma. The present method could be applied to patients with pain and be used for the clinical research or therapeutic drug monitoring of pregabalin.

Saturated Metabolism of Voriconazole N-Oxidation Resulting in Nonlinearity of Pharmacokinetics of Voriconazole at Clinical Doses.

Metabolic saturation of voriconazole based on the trough plasma concentrations of voriconazole and its major metabolite N-oxide were evaluated according to CYP2C19 genotypes in 58 Japanese patients receiving voriconazole (median dose; 200 mg twice daily) for prophylaxis or treatment. Predose trough plasma concentrations of voriconazole and N-oxide were monitored on day 5 d or later after initiation of voriconazole treatment. Large interindividual variations in trough plasma concentrations of voriconazole and N-oxide were observed. Dose-normalized trough plasma concentrations of voriconazole were strongly correlated with its absolute trough concentrations, and the straight regression line between them intersected close to the origin of the coordinates. No significant correlation was observed between the trough plasma concentrations of voriconazole and N-oxide. The inverse value of the metabolic ratio of N-oxide to voriconazole was strongly correlated with the absolute trough voriconazole concentrations. No significant differences in the trough plasma concentrations of voriconazole and N-oxide or the metabolic ratio of N-oxide to voriconazole between the CYP2C19 genotypes were observed. Saturated metabolism of voriconazole N-oxidation rather than CYP2C19 genotypes contributed to the nonlinear pharmacokinetics. The metabolic process converting voriconazole to N-oxide was saturated at the clinical dose.

Impact of CYP3A5*3 on plasma exposure and urinary excretion of fentanyl and norfentanyl in the early postsurgical period.

BACKGROUND: The pharmacokinetic characteristics of intravenous fentanyl have not been fully clarified in the early postsurgical period. The aim of this study was to evaluate the plasma exposure and urinary excretion of fentanyl and norfentanyl according to cytochrome P450 (CYP) 3A5 genetic polymorphism. METHODS: Fifty-two adult Japanese postoperative patients receiving a continuous intravenous fentanyl infusion were enrolled. Plasma concentrations of fentanyl and norfentanyl were determined at 24 hours after the operation, and their urinary excretion from 12 to 36 hours was evaluated. RESULTS: Plasma concentrations of fentanyl normalized for infusion rate were significantly higher in the *3/*3 group than in the *1 carrier group. The plasma concentration ratio of norfentanyl to fentanyl was significantly lower in the *3/*3 group than in the *1 carrier group. Urinary excretion rates of fentanyl and norfentanyl were 4.4% and 71%, respectively, and no significant differences were observed between the CYP3A5 genotypes. Renal clearance ratios of fentanyl and norfentanyl to creatinine were 0.34 and 3.4, respectively. There were no significant differences in the renal clearance ratios between the genotypes. Free fractions of fentanyl and norfentanyl in human plasma were 4.9% and 95%, respectively. Total and nonrenal clearance of fentanyl were significantly lower in the *3/*3 group than in the *1 carrier group. CONCLUSIONS: CYP3A5*3 affected the plasma exposure of fentanyl but not urinary excretion in our postoperative patients. The renal clearance ratios of fentanyl and norfentanyl to creatinine were much higher than their free fractions in plasma. These findings suggest a slight contribution of renal tubular secretion of fentanyl and norfentanyl to their plasma exposures.

Simple and validated UHPLC method coupled to UV detection for determination of daptomycin in human plasma and urine.

Daptomycin, a lipopeptide antibiotic with excellent activity against Gram-positive bacteria, is excreted primarily by the kidneys. Development of effective chromatographic methodologies for the determination of daptomycin in human specimens is necessary for clinical use. This study developed a simple and validated ultra-high-performance liquid chromatography method coupled to ultraviolet detection for determination of daptomycin in human plasma and urine. After the pretreatments involving protein precipitation, the supernatants were separated using a 2.3 µm particle size octadecylsilyl column, and the run time was 1 min. The calibration curves were linear over the concentration ranges of 2-200 mg/L for plasma and 25-300 mg/L for urine. Intra- and inter-assay precision and accuracy values of plasma were within 13.5 and 92-100% and within 10.7 and 100-107%, respectively. Those of urine were within 5.0 and 101-104% and within 3.7 and 100-101%, respectively. The validated method was applied to the determination of plasma and urine samples in patients receiving 4-6 mg/kg of intravenous daptomycin, resulting in sufficient sensitivity for evaluating the plasma exposure and urinary excretion. In conclusion, the present method with acceptable analytical performance can be helpful for evaluating the pharmacokinetic disposition of daptomycin in clinical settings.

Plasma exposure of free linezolid and its ratio to minimum inhibitory concentration varies in critically ill patients.

The clinical implications of free linezolid monitoring have not been fully clarified in critically ill patients. The aim of this study was to evaluate the variability in pharmacokinetics of free linezolid and its relationship with susceptibility to meticillin-resistant Staphylococcus aureus (MRSA) in critically ill patients. Twenty critically ill MRSA-infected patients receiving intravenous linezolid were enrolled. Blood specimens were collected by 12-h sampling after dosing at Day 7. The medians (interquartile range) of the minimum free concentration, area under the concentration-time curve of total and free linezolid from 0 to 24 h (AUC(0-24) and fAUC(0-24), respectively) and percentage bound were 9.9 µg/mL (5.2-15 µg/mL), 495 µgh/mL (291-695 µgh/mL), 385 µgh/mL (242-528 µgh/mL) and 23% (15-28%), respectively. The medians of the AUC(0-24) and fAUC(0-24) to minimum inhibitory concentration ratios (AUC/MIC and fAUC/MIC) were 248 (144-347) and 192 (109-264), respectively. Two patients failed to achieve adequate levels of AUC/MIC and fAUC/MIC for linezolid. The percentage bound of linezolid in hypoalbuminaemic patients was significantly lower than in non-hypoalbuminaemic patients. A significant correlation was observed between fAUC(0-24) and creatinine clearance. In addition, the fAUC(0-24) was correlated with the minimum free concentration. In conclusion, the plasma level of free linezolid was variable in critically ill patients with renal dysfunction and hypoalbuminaemia. This finding suggests that the monitoring of free linezolid is necessary in critically ill patients.

Peripheral capillary nonperfusion and full-field electroretinographic changes in eyes with frosted branch-like appearance retinal vasculitis.

We report a patient with frosted branch-like appearance retinal vasculitis associated with peripheral capillary nonperfusion and full-field electroretinographic changes. A 62-year-old man presented with sudden bilateral decreased vision accompanied by headaches. His best-corrected visual acuity was 0.01 in both eyes. Fundus examination and fluorescein angiography showed bilateral frosted branch-like appearance retinal vasculitis, and spectral-domain optical coherence tomography showed severe macular edema in both eyes. The cerebrospinal fluid analyses showed an increased lymphocyte count and protein levels. He was treated with systemic corticosteroid therapy, and his best-corrected visual acuity improved to 0.8 OD and 1.0 OS at 6 months after onset. However, fluorescein angiography showed a lack of capillary perfusion in the periphery, and the oscillatory potentials on full-field electroretinography were severely reduced in both eyes. These findings indicated extensive retinal ischemia and inner retinal dysfunction, and that fluorescein angiography and full-field electroretinograms can be useful during follow-up of eyes with frosted branch-like appearance retinal vasculitis.

Hydroxy-itraconazole pharmacokinetics is similar to that of itraconazole in immunocompromised patients receiving oral solution of itraconazole.

BACKGROUND: The pharmacokinetic variability of hydroxy-itraconazole (OH-ITZ), an active metabolite of itraconazole (ITZ), is not fully known. METHODS: Oral solution of ITZ was administered in 46 immunocompromised patients as a single 200 mg dose for at least 12 days. The plasma concentrations of ITZ, active OH-ITZ, and keto-itraconazole (keto-ITZ), an inactive metabolite, 12 h after administration were determined by LC-UV or LC-MS/MS. RESULTS: The mean±SD of plasma concentrations of ITZ, OH-ITZ, and keto-ITZ were 833±468, 798±454, and 3.94±2.68 µg/l, respectively. A greater correlation coefficient was observed between plasma concentrations of ITZ and OH-ITZ (r=0.90, P<0.01) than between OH-ITZ and keto-ITZ (r=0.44, P<0.01). Plasma concentration of OH-ITZ was inversely correlated with concentration ratio of keto-ITZ to OH-ITZ (r=-0.52, P<0.01). Plasma concentrations of ITZ and OH-ITZ were correlated with serum concentration of albumin (r=0.36, P=0.01 and r=0.37, P=0.01) and estimated glomerular filtration rate (r=-0.27, P=0.08 and r=-0.35, P=0.02). CONCLUSIONS: The pharmacokinetic variability of OH-ITZ was associated with saturated metabolism to keto-ITZ, serum concentration of albumin, and renal function in immunocompromised patients. The plasma concentration of OH-ITZ was strongly correlated with that of ITZ. Prevention of fungal infections can be improved by determining the plasma concentration of ITZ or OH-ITZ.

Simple and rapid HPLC-UV method using an ultrafine particle octadecylsilane for determination of residual fentanyl in applied Durotep MT transdermal matrix patches and its clinical application.

A few complicated and time-consuming methods are available for the determination of residual fentanyl in Durotep MT transdermal patches, however, their application to clinical settings is limited. The aim of this study was to develop a simple and rapid HPLC-UV method using an ultrafine particle octadecylsilane (ODS) for the determination of residual fentanyl in applied Durotep MT transdermal matrix patches. Patch extraction involved sonicating a shredded Durotep MT patch in acetonitrile for 15 min. Fentanyl separation was completed within 2 min using a 2.3-µm particle ODS column (50 × 4.6 mm i.d.) at a flow rate of 1.5 mL/min. No peaks interfering with fentanyl (1.27 min) and papaverine (0.89 min) as an internal standard were observed. The calibration curve for fentanyl was linear over the range of 0.015-9.0 mg as a Durotep MT patch. The intra- and inter-assay precisions and accuracies of each patch were within 5.3% and 103.9-110.5% and within 8.2% and 97.1-104.3%, respectively. The validated method was applied to determine residual fentanyl in Durotep MT patches used in 35 cancer patients. Although the plasma fentanyl concentration was significantly correlated with its measured absorption rate, the measured absorption rate normalized fentanyl concentration showed a large inter-individual variation. The validated simple and rapid HPLC-UV method established in the present study is helpful for evaluating the absorption rate of fentanyl in patients receiving Durotep MT patches.

Impact of concomitant antacid administration on gabapentin plasma exposure and oral bioavailability in healthy adult subjects.

The aim of this open-label, randomized, and 3-period crossover study was to evaluate the influences of concomitant antacid administration on the plasma disposition, intestinal absorption, and urinary excretion of gabapentin in humans. Gabapentin (200 mg) was orally administered alone, with 1 g magnesium oxide (MgO), or with 20 mg omeprazole to 13 healthy adult subjects. Oral bioavailability (BA) of gabapentin was estimated by 24-h urine collection. The C(max), T(max) and AUC(0-∞) of gabapentin + MgO were significantly lower than that of gabapentin alone (by 33%, 36% and 43%, respectively) and gabapentin + omeprazole (by 29%, 46% and 40%, respectively). In contrast, no significant differences were observed in the plasma disposition parameters of gabapentin between the treatments with and without omeprazole. The gabapentin BA in the MgO treatment was significantly lower, by 32% and 39%, compared to the gabapentin alone and with omeprazole treatment, respectively. There was no significant difference in the gabapentin BA between the gabapentin alone and with omeprazole treatment. Concomitant MgO and omeprazole did not affect the renal clearance of gabapentin. In conclusion, concomitant MgO decreased the gabapentin exposure through the reduction of intestinal absorption extent and rate. This reduction may be independent of the suppression of gastrointestinal acidification caused by antacids.

Impact of CYP3A5 and ABCB1 gene polymorphisms on fentanyl pharmacokinetics and clinical responses in cancer patients undergoing conversion to a transdermal system.

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.

Rapid simultaneous determination of voriconazole and its N-oxide in human plasma using an isocratic high-performance liquid chromatography method and its clinical application.

OBJECTIVES: The aim of this study was to develop a simultaneous determination method for voriconazole (VRCZ) and its N-oxide (VNO) in human plasma and to apply it to clinical samples. DESIGN AND METHODS: Plasma specimens were deproteinized with acetonitrile and then injected into an HPLC-UV system. VRCZ and VNO were separated on an ODS column filled with 2.3-µm particles using an isocratic mixture of acetonitrile/methanol/phosphate buffer 25/10/65 (v/v/v). Plasma concentrations of VRCZ and VNO in 25 patients were determined. RESULTS: Both VRCZ and VNO were linear (r>0.999) over the concentration ranges of 0.1-8.0mg/L. The run time for quantification of the analytes was 4 min. Interindividual variation in the plasma concentration of VRCZ that ranged from less than 0.1 to 6.96 mg/L was observed. VNO concentrations weakly depended on VRCZ dosage. CONCLUSIONS: The present method can contribute to the optimization of antifungal therapy using VRCZ.