Trans-stimulation effect on tetraethylammonium (an organic cation) transport was examined in rat renal brush-border membrane vesicles. The uptake of [14C]tetraethylammonium at pH 6.0-8.5 was stimulated by preloading the membrane vesicles with unlabeled tetraethylammonium. When the uptake was measured in preloaded membrane vesicles in the presence of carbonyl cyanide p-trifluoromethoxyphenylhydrazone, stimulation was observed at high pH but not at low pH. These results suggest that the mechanisms of the trans-stimulation effect on organic cation transport are different depending on the pH. When pH is low, the trans-stimulation is due to generation of an outward H+ gradient, which in turn stimulates [14C]tetraethylammonium uptake by H(+)-[14C]tetraethylammonium exchange. In contrast, when pH is high, the stimulation is due to direct exchange of tetraethylammonium for [14C]tetraethylammonium.
The pharmacokinetics of vancomycin was retrospectively examined based on trough concentrations obtained during routine therapeutic drug monitoring to examine possible pharmacokinetic differences between adult Japanese cancer and non-cancer patients with various degrees of renal function. A total of 231 data points from 65 cancer patients and 41 non-cancer patients were collected, and patients' background, vancomycin dose, and vancomycin clearance estimated by an empirical Bayesian method were summarized. Regarding the patients' characteristics and clinical laboratory test data, no clear differences were found between the two groups. The relationship between vancomycin clearance and creatinine clearance were similar between the groups, suggesting little effect of malignancy on vancomycin clearance. After the sub-group comparisons regarding fluid retention and cancer type, no clear differences were found in the vancomycin clearance versus creatinine clearance relationship. We conclude that the initial dose of vancomycin should not necessarily be adjusted for cancer patients. For individualized vancomycin-based therapy, dose adjustment at the appropriate time is important according to information from routine therapeutic drug monitoring and clinical laboratory tests, and to observations of the efficacy, nephrotoxicity, and other conditions in each patient.
Sunitinib, a multitargeted tyrosine kinase inhibitor, offers favorable therapeutic outcomes to patients with advanced renal cell carcinoma. However, to maximize the clinical benefits, an effective therapeutic management strategy with dose optimization is essential. The objectives of this analysis were to describe the pharmacokinetics (PK) of sunitinib by a population PK approach and to quantitatively evaluate the effect of potential predictive factors including ABCG2 genotype on the PK of sunitinib.Plasma concentration-time profiles at 3 consecutive days including a total of 245 sunitinib plasma concentrations were available from 19 Japanese patients with renal cell carcinoma. Blood samples were collected on days 2, 8, and 15 after the start of the therapy. Population PK analysis was performed using NONMEM 7.2. Body weight, gender, and genotype of ABCG2 421C>A were evaluated as potential covariates. Interoccasion variability (IOV) among the 3 sampling days was also assessed as a random effect parameter.The sunitinib PK profiles were best described by a 1-compartment model with first-order absorption. The ABCG2 421C>A genotype was identified as a significant covariate for the prediction of oral clearance (CL/F). No significant improvement in model fit was observed by including body weight and/or gender. A systematic difference in estimated population CL/F was observed between days 2 and 8, which was quantified as approximately 30% decrease over time. This difference was described as a covariate for CL/F in the model. IOV included as a random effect parameter significantly improved the model fit.This analysis provides a population PK model of sunitinib with the ABCG2 421C>A genotype as a predictive covariate for CL/F. It also suggests that IOV and change of CL/F over time need to be considered to predict the sunitinib PK more accurately. These findings will be implemented to optimize the pharmacotherapy of sunitinib.
Infant mice (2 to 4 days old) were exposed to living Mycoplasma pneumoniae. The organisms were isolated in the order of 10(3) to 10(4) colony-forming units from the lungs of mice for 2 weeks after infection. Mononuclear cell infiltration was present in the lungs of infected mice. The specific IgG antibodies to membrane proteins of M. pneumoniae in the sera of infected mice were detected by enzyme-linked immunosorbent assay for about 800 days. In immunoblotting analysis, a 160-kilodalton (kDa) protein strongly reacted with the infected mouse sera. The dams immunized with membrane proteins conferred passive immunity on their offspring via colostrum. Specific IgG antibody appeared in the serum of infant mice that were given mouse anti-M. pneumoniae serum or convalescent human patient serum orally. These mice were also protected from challenge with M. pneumoniae. The immunoblotting patterns of patient sera were similar to those of infected mouse sera. The infant mouse model may be useful to investigate the host immune responses to M. pneumoniae.
Human organic cation transporter 2 (hOCT2; SLC22A2) is abundantly expressed in the kidney, and it plays important roles in the renal tubular secretion of cationic drugs. Although the transport characteristics of hOCT2 have been studied extensively, there is no information available for the transcriptional regulation of hOCT2. The present study was undertaken to identify the cis-element and trans-factor for basal expression of hOCT2. The transcription start site was located 385 nucleotides above the translation start site by using 5′-rapid amplification of cDNA ends. An approximately 4-kilobase fragment of the hOCT2 promoter region was isolated and the promoter activities were measured in the renal epithelial cell line LLC-PK1. A deletion analysis suggested that the region spanning –91 to –58 base pairs was essential for basal transcriptional activity. This region lacked a TATA-box but contained a CCAAT box and an E-box. Electrophoretic mobility shift assays showed that specific DNA/protein complexes were present in the E-box but not in the CCAAT box, and supershift assays revealed that upstream stimulatory factor 1 (USF-1), which belongs to the basic helix-loop-helix-leucine zipper family of transcription factors, bound to the E-box. Mutation of the E-box resulted in a decrease in hOCT2 promoter activity, and overexpression of USF-1 enhanced the hOCT2 promoter activity in a dose-dependent manner. This article reports the first characterization of the hOCT2 promoter and shows that USF-1 functions as a basal transcriptional regulator of the hOCT2 gene via the E-box.
2549 Background: Erlotinib is a potent EGFR tyrosine kinase inhibitor, currently used to treat non-small cell lung cancer (NSCLC). Erlotinib shows a significant pharmacokinetic (PK) variability and has various adverse reactions including fatal interstitial lung disease (ILD). We aimed to investigate population PK of erlotinib and to explore the relationship between early drug exposure and the safety and antitumor activity in clinical practice setting. Methods: A total of 60 patients with NSCLC treated with erlotinib (150 mg/day) were enrolled in this study. Full PK profiles of erlotinib and its active metabolite OSI-420 were evaluated on day 1 and at steady state (ss) on day 8. The CYP3A5*3 and ABCG2 421C>A polymorphisms were genotyped, and EGFR mutation status in tumors (exons 18-21) was obtained from medical records if available. Population PK analysis was performed with NONMEM program. The objective response rate (ORR) was assessed using RECIST criteria. Results: The metabolic ratio of erlotinib to OSI-420 was correlated with the CYP3A5*3 genotype. The apparent clearance of erlotinib and OSI-420 were significantly decreased in patients with the ABCG2 421A allele. The cumulative incidences of grade > 2 rash and diarrhea during the first month were significantly higher in patients with high AUCss (> 37.2 µg*h/mL) than others (50% v 18%, P < .01 and 29% v 4%, P < .01, respectively). Furthermore, the ABCG2 genotype was related to the incidence of diarrhea but not rash. In 2 patients with ILD-like events, trough levels were extensively elevated on the day of the events (> 3.0 µg/mL). The ORR in patients with EGFR mutations did not correlate with AUCss (low group, 82%; high group, 90%), whereas there appeared to be a greater response for high group versus low group within the wild-type patients (33% v 11%). Conclusions: Erlotinib disposition can be affected by CYP3A5 and ABCG2, and early drug exposure would be associated with the development of adverse events while having a less impact on tumor response particularly in NSCLC patients with EGFR mutations. Genome-based and PK-guided erlotinib therapy should be valuable to minimize toxicity and maximize clinical efficacy.
