We studied the transport mechanism of pirarubicin (THP) in HL60 and its THP-resistant (HL60/THP) cells, which showed no expression of mdr1 mRNA on Northern blot analysis. Under physiological conditions, the uptake of THP by both types of cell was time- and temperature-dependent. The amount of drug transport in the resistant cells was significantly less than that in the parent cells within 3 min of incubation. THP uptake was significantly higher in the presence than in the absence of 4 mM 2,4-dinitrophenol (DNP) in glucose-free Hanks' balanced salt solution in both HL60 and HL60/THP cells and the increases were approximately equal. In the presence of DNP, the uptake of THP by both types of cell was concentration-dependent, and there were no significant differences in the apparent kinetic constants (Michaelis constant (Km), maximum velocity (Vmax) and Vmax/Km) for THP uptake between HL60 and HL60/THP cells. Additionally, THP transport was competitively inhibited by its analogue doxorubicin. The efflux of THP from HL60/THP cells was significantly greater than that from HL60 cells, and the release from both types of cell was completely inhibited by decreasing the incubation temperature to 0 degrees C and by treatment with DNP in glucose-free medium. In contrast, the P-glycoprotein inhibitors verapamil and cyclosporin A did not inhibit THP efflux. However, genistein, which is a specific inhibitor of multidrug resistance-associated protein (MRP), increased the THP remaining in the resistant cells, and the value was approximately equal to that of the control group in the sensitive cells. These results suggest that THP is taken up into HL60 and HL60/THP cells via a common carrier by facilitated diffusion, and then pumped out in an energy-dependent manner. Furthermore, the accelerated efflux of THP by a specific mechanism, probably involving MRP, other than the expression of P-glycoprotein, resulted in decreased drug accumulation in the resistant cells, and was responsible, at least in part, for the development of resistance in HL60/THP cells.
Lenalidomide (Len), an immunomodulatory drug, has significant clinical activity in patients with relapsed and refractory multiple myeloma (MM), and it is usually administered at a dose of 25 mg daily. For Len to exert its therapeutic effects with minimum adverse effects, it is important to determine the most suitable dosage on the basis of the physiques and body surface area (BSA) of patients. We investigated the relationship between pharmacokinetic variability of this drug and its toxicity and therapeutic efficacy. The institutional review boards and ethics committees at both participating centers approved the study protocol and all patients provided written informed consent. Thirteen Japanese patients with relapsed and refractory MM were enrolled in this study. They were treated with Len at 10-25 mg for 21 days every 4 weeks. The dose of Len administered to patients with renal dysfunction was reduced according to consensus statements on the optimal use of Len. Dexamethasone at 8-40 mg weekly was added to each drug cycle. Peripheral blood was collected three hours after Len administration in the first cycle and the plasma concentration of Len was evaluated using high performance liquid chromatography. Response and progression were assessed according to the International Myeloma Working Group criteria and the severity of adverse events was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. The median values of age (years) and estimated creatinine clearance (eCLcr, mL/min) of the 13 enrolled patients (male to female ratio=5:8) were 69 and 66.3, respectively. The number of patients in stages I, II, and III or the unknown stage of the International Staging System were 8, 1, 2, and 2, respectively. The number of the patients who achieved the best responses during three cycles of treatment were one (7.7%) in complete response, four (30.8%) in partial response, and eight (61.5%) in stable disease. The percentage of hematological adverse events (Grade 3/4) was 38.5% and no non-hematological events (Grade 3/4) were observed. The Len concentration ranged from 172.5 ng/mL to 555.6 ng/mL with a median concentration of 341.8 ng/mL. eCLcr values did not correlate with Len concentrations, but significantly correlated with C/D ratios (p <0.005, Figure 1). We next evaluated the correlation between Len concentration and the severity of adverse events. The percentage of patients with any Grade 1/2 adverse event and the percentage of those with Grade 3/4 adverse events were 61.5% (8/13) and 38.5% (5/13), respectively. A Receiver Operating Characteristic curve analysis of Len concentrations was used to determine an optimal cutoff value with the Youden index. The percentage of severely of any Grade 3/4 adverse event for patients with ≥ 320 ng/mL Len was 62.5% (5/8), and that of patients with <320 ng/mL was zero (0/5). The Fisher's exact test demonstrated that the severity of adverse effects significantly correlated with the Len concentration (Table 1, p <0.05). However, there was no correlation between Len concentrations and best responses. These findings indicate that it is possible to avoid severe adverse events without reducing therapeutic efficacy by monitoring Len concentrations. In conclusion, this pilot study suggests that it is important to determine the Len dosage on the basis of its plasma concentration. This issue should be clarified further in a large-scale study. Disclosures Kado: Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment. Kitazawa:Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment. Fuchida:Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment. Okano:Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment. Hatsuse:Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment. Murakami:Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment. Ueda:Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment. Kokufu:Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment. Shimazaki:Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment.
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