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Vincristine (VCR) is a key drug for treating various malignancies. However, few data are available on the pharmacokinetics of VCR, especially in adult patients. The objective of this study was to clarify the population pharmacokinetics and exposure–response relationships of VCR in adult malignant lymphoma patients. Blood samples were collected from patients who were administered R-CHOP-like regimens, and the VCR plasma concentration was determined using liquid chromatography–mass spectrometry. Using NONMEM software, population pharmacokinetic parameters were estimated, and covariates were evaluated. The relationships between the individual parameters and adverse events or therapeutic effects were also investigated. Plasma concentrations were measured in 30 patients. In the final population pharmacokinetics model, body surface area and age were incorporated into clearance as significant covariates. The inter-individual variations in clearance and volume of distribution in the central and third compartments were 17.0, 26.6, and 66.3%, respectively, and the residual variability in the plasma concentration was 23.8%. Although the variability observed in the volume of distribution was large, good predictability was obtained in the individual estimation. The severity of anemia and peripheral neuropathy was correlated with clearance and peak concentration, respectively (adjusted P = 0.040 and 0.024, respectively). In diffuse large B cell lymphoma patients, those with higher area under the curve and dose experienced longer progression-free survival (P = 0.023 and 0.013, respectively). The population pharmacokinetics of VCR were evaluated in adult malignant lymphoma patients. VCR pharmacokinetic data could explain in part the adverse events and prognosis of these patients.

Although combination therapy with the oral fluoropyrimidine anticancer drug S-1 and the anticonvulsant phenytoin (PHT) is known to increase blood levels of PHT and the risk of intoxication, reports on long-term monitoring of blood levels of PHT during combined S-1 and PHT treatment and a thorough understanding of their interaction are lacking. This report aims to describe interactive effects of S-1 and PHT through long-term therapeutic drug monitoring of PHT. A 72-year-old male had been prescribed oral PHT (130 mg/day) for over 20 years and started receiving S-1 therapy (80 mg/day for 4 weeks, followed by a 2-week rest) as postoperative adjuvant chemotherapy for gastric cancer. The blood PHT level was continuously monitored. Prior to receiving S-1, the patient's blood PHT concentration was 6.0 μg/ml, but it increased during S-1 therapy, reaching 22.9 μg/ml on day 84 (during a rest period of second cycle S-1 therapy). After reducing his PHT dosage to 100 mg/day, it never reached toxic levels (4.0-10.4 μg/ml). It was difficult to keep blood PHT concentrations constant because of the time lag between the period of combined use of S-1 and PHT and the timing of manifestation and disappearance of the drug interaction. The DIPS probability scale indicated a highly probable interaction between S-1 and PHT. We conclude that, when S-1 and PHT are used concurrently, occurrence and disappearance time of their interaction need to be predicted to maintain an effective and safe PHT concentration.

As the effect of the filling process of portable pumps on the homogeneity of drug concentrations had not been investigated,in this study,we examined the influence of the filling process of the anticancer agent 5-fluorourcil (5-FU) and saline in this respect.We used 3 types of pump and filled the pump in 3 different ways (5-FU first and then saline,saline first and then 5-FU,and mixing 5-FU and saline beforehand and then filling).There was a significant variation in the 5-FU concentration when 5-FU and saline were added separately but the drug concentration did not vary when 5-FU and saline were mixed before filling the pumps.The result also varied with the type of pump.Our findings suggested that the drug and saline were not mixed uniformly in some types of pump when 5-FU and saline were added separately.Therefore,it is important to mix the drug and saline well before filling pumps.

During cancer chemotherapy,myelosuppression is a frequently observed toxicity manifestation which may sometimes cause severe infections.In this regard,though leukopenia-induced infections are more closely related to neutrophil counts than leukocyte counts,it is important to evaluate both leukocyte counts and neutrophil counts as markers of myelosuppression.Neutrophil counts,however,are sometimes estimated to be half leukocyte counts without conducting differential leukocyte counts.In the present study,the authors evaluated the necessity of differential leukocyte counts during cancer chemotherapy using pooled laboratory data at the University of Fukui Hospital.Variation in the percentage of neutrophils in leukocytes was observed in each leukocyte range,with the neutrophil count decreasing in pace with decreases in the leukocyte count.As an alternative index to the neutrophil count,the utility of the leukocyte count is thus considered to be low in cancer chemotherapy.There was also a divergence between adverse event grade between neutrophil and leukocyte numbers.In addition,neutrophil counts in 14.8% of the patients (26)were less than 1000/μL in spite of the fact that their leukocyte counts were higher than 3000/μL,and it was noted that 23 of them had undergone a paclitaxel-containing regimen.These results suggested that leukocyte differential counts should be measured during cancer chemotherapy,especially during the nadir period and when receiving chemotherapy containing paclitaxel.

The enterohepatic recycling of a drug consists of its biliary excretion and intestinal reabsorption, which is sometimes accompanied by hepatic conjugation and intestinal deconjugation reactions. β-Glucuronidase, an intestinal bacteria-produced enzyme, can break the bond between a biliary excreted drug and glucuronic acid. Antibiotics such as ciprofloxacin can reduce the enterohepatic recycling of glucuronide-conjugated drugs. In this study, we established an in vitro system to evaluate the β-glucuronidase-mediated deconjugation of the irinotecan metabolite SN-38-G to its active SN-38 form and the effect of ciprofloxacin thereon. SN-38 formation increased in a time-dependent manner from 5 to 30 min. in the presence of β-glucuronidase. Ciprofloxacin and phenolphthalein-β-D-glucuronide (PhePG), a typical β-glucuronidase substrate, significantly decreased SN-38-G deconjugation and, hence SN-38 formation. Similarly, the antibiotics enoxacin and gatifloxacin significantly inhibited the conversion of SN-38-G to SN-38, which was not observed for levofloxacin, streptomycin, ampicillin and amoxicillin/clavulanate. Ciprofloxacin showed a dose-dependent inhibitory effect on the β-glucuronidase-mediated conversion of SN-38-G to SN-38 with a half-maximal inhibitory concentration (IC50 ) value of 83.8 μM. PhePG and ciprofloxacin afforded the inhibition in a competitive and non-competitive manner, respectively. These findings suggest that the reduction in the serum SN-38 concentration following co-administration of ciprofloxacin during irinotecan treatment is due, at least partly, to the decreased enterohepatic circulation of SN-38 through the non-competitive inhibition of intestinal β-glucuronidase-mediated SN-38-G deconjugation.

Cyclosporin A pharmacokinetics was studied in rats with cisplatin-induced acute renal failure (ARF) using microemulsion preconcentrate (MEPC) and completely dissolved formulations. Although the pharmacokinetics of cyclosporin A was unchanged after intravenous administration, maximum concentration of cyclosporin A in ARF rats was significantly reduced to 608+/-62 and 999+/-189 ng/ml compared with 1720+/-142 and 1832+/-250 ng/ml in controls after oral administration of MEPC and completely dissolved formulations, respectively. In an in situ intestinal loop sac study, the amount absorbed plus metabolized and the blood concentration of cyclosporin A were similar between control and ARF rats, and taurocholic acid, one of the bile acids, significantly increased absorption of cyclosporin A using the MEPC formulation in both control and ARF rats; the amount absorbed plus metabolized with taurocholic acid was increased to 137 and 186%, and simultaneously the blood concentration was increased to 155 and 158% of that without taurocholic acid in control and ARF rats, respectively. The bile flow in ARF rats was decreased compared with that in controls. These results suggested that renal dysfunction decreased the absorption of cyclosporin A in spite of the MEPC formulation, and the alternation of bile secretion partly affected the absorption rate of cyclosporin A in the gastrointestinal tract.

Organosilicon polymers have attracted considerable attention as a new class of functional polymers of the next generation because of their unique electronic and optical properties originating from the delocalization of σ-σ * conjugated electrons along the Si-Si main chain of polysilane. Thus, for these polymers, oxygen is the most remarkable impurity. Nevertheless, the determination of oxygen in any organic material is extremely difficult. Especially, for oraganosilicon compounds, conventional methods do not give good results. In this study we investigated the reason for the low recoveries of organosilicon compounds by several kinds of determination methods, and developed a new determination method involving on inert-gas fusion equipped converter, which includes platinum-carbon. According to our method, oxygen in organosilicon polymers can be determined quantitatively. We confirmed that our new method is applicable not only to organosilicon materials, but also to organic and organometallic compounds as well as inorganic materials.

Granulocyte colony-stimulating factor administration is an important component of supportive therapy in chemotherapy-induced leukopenia. Although patient response to granulocyte colony-stimulating factor administration is known to vary, the factors responsible for poor response have not been identified.To identify the predictors of the responses of patients with solid tumors to granulocyte colony-stimulating factor.A 600-bed university hospital offering secondary and tertiary care in Japan.This retrospective cohort study examined the response of 181 patients with solid tumors who were administered prophylactic granulocyte colony-stimulating factor for the first time after they developed severe grade 3/4 leukopenia (white blood cell count2,000 × 10(-9)/L) because of adjuvant or neoadjuvant chemotherapy. The granulocyte colony-stimulating factor response was defined as the length of the leukocyte recovery period, which was assessed as the period within which the normal white blood cell count (white blood cell count3,000 × 10(-9)/L) is reached after the first dosage of granulocyte colony-stimulating factor. After classification of the patients as either poor or normal granulocyte colony-stimulating factor responders according to the confidence interval of the recovery period, their characteristics were compared.The time for recovery to normal white blood cell count was 2-7 days (90 % confidence interval), and the cutoff value for differentiating poor responders (n = 14) from normal responders (n = 167) was 8 days. Univariate analysis identified previous radiotherapy, number of chemotherapy courses, high granulocyte colony-stimulating factor dosage, and hypoalbuminemia to be significantly associated with granulocyte colony-stimulating factor response. Multivariate analysis identified undergoing four or more chemotherapy courses (odds ratio = 5.09; 95 % confidence interval, 1.14-22.71) and heart failure (odds ratio = 5.96; 95 % confidence interval, 1.09-32.57) to be significantly associated with poor granulocyte colony-stimulating factor response.Undergoing four or more chemotherapy courses and heart failure are independent risk factors for poor response to granulocyte colony-stimulating factor. These findings may help prevent the complications of leukopenia during chemotherapy and highlight the need to develop better strategies for preventing and treating infectious disease in patients undergoing granulocyte colony-stimulating factor administration.

Background: Myelotoxicity, a major toxicity of vinorelbine, may be related to the degree of one's exposure to vinorelbine. In theory, clarithromycin has the potential to alter vinorelbine's pharmacokinetics by inhibiting CYP3A and/or P-glycoprotein; this may result in massive exposure to vinorelbine and severe toxicity. To date, macrolide–vinorelbine drug interactions have not been reported. Objective: To estimate the clinical risk of a interaction between vinorelbine and clarithromycin. Methods: In a retrospective cohort study, we searched computerized medical records of patients who had been administered vinorelbine in the University of Fukui Hospital. The study cohort was defined as all patients with non–small-cell lung cancer who received vinorelbine between May 30, 2003, and January 31, 2008. The treatment courses were classified according to whether or not clarithromycin was concomitantly administered with vinorelbine. Nadir neutrophil counts were recorded as the major outcomes. Vinorelbine–clarithromycin interaction was defined as a significant increase in the risk of severe neutropenia when the 2 drugs were administered concomitantly. Results: A total of 12 (63.2%) and 11 (27.5%) episodes of grade 3/4 neutropenia occurred among the patients who were and were not administered clarithromycin, respectively. The incidence of grade 4 neutropenia was higher in the group administered clarithromycin than in those who did not receive it (31.6% vs 2.5%; p = 0.0033). Vinorelbine dose, concomitant clarithromycin administration, and female sex were significantly correlated with severe neutropenia, with unadjusted odds ratios of 0.07 (95% CI 0.01 to 0.59), 4.52 (95% CI 1.41 to 14.45), and 4.55 (95% CI 1.39 to 14.29), respectively. Conclusions: Compared with patients who are administered vinorelbine alone, patients who are administered clarithromycin during chemotherapy with vinorelbine are at a higher risk for severe neutropenia. Physicians should educate their patients about this interaction. If possible, clarithromycin administration should be avoided in patients who will undergo chemotherapy with vinorelbine in the near future. However, further prospective pharmacokinetic studies are required to confirm this interaction.

The impact of lower serum albumin levels on teicoplanin pharmacokinetics has not been previously determined. The authors assessed the relationship between total and free concentrations of teicoplanin in serum samples obtained from patients receiving teicoplanin therapy for Gram-positive bacterial infections. In addition, the authors determined the contribution of serum albumin concentrations to the unbound fraction of teicoplanin. One hundred ninety-eight serum samples were obtained from 65 patients undergoing routine therapeutic drug monitoring of teicoplanin. Free serum teicoplanin was separated by ultrafiltration, and total and free serum concentrations of teicoplanin were determined by a fluorescence polarization immunoassay. Regression analysis was then performed to build a prediction model for the free serum teicoplanin concentration from the total serum teicoplanin concentration and the serum albumin level using the first 132 samples. The predictive performance of this model was then tested using the next 66 samples. Free serum teicoplanin concentrations (Cf) (mug/mL) were predicted using a simple model constructed using total serum teicoplanin (Ct) (mug/mL) and albumin concentrations (ALB) (g/dL): Cf = Ct/(1 + 1.78 * ALB). This model could estimate free serum teicoplanin concentrations with a small bias and an acceptable error. The measured free level of teicoplanin will lie between 0.63 and 1.38 times the predicted concentration in 95% of cases. Serum albumin level plays a major role in the variability of the fraction unbound of teicoplanin. This model can reliably estimate free serum teicoplanin concentrations more easily than by using direct measurements.