Pharmacokinetic (PK) modeling has been proposed as a means to improve the efficiency of drug development. It is difficult to develop an appropriate pharmacokinetic model if the lower limit of quantification (LLOQ) of the assay of the plasma drug concentration is high. The mathematical method of determining the plasma drug concentration below the LLOQ was discussed previously. 1,2) The method of analyzing the data including the urine concentration to construct the PK model that cannot be constructed using only plasma concentration data has also been reported.3) Not only the plasma concentration data but also urine and bile data collected over time provided information that was used as basis for the development of a PK model. Although the use of serum or plasma concentration-time profiles was primarily recommended, the use of urinary and/or biliary excretion data was regarded as an alternative approach if the bioanalytical method lacked the appropriate sensitivity to adequately characterize the serum or plasma concentration-time profile. This approach is considered to be used for the analysis of plasma concentration-time profile under LLOQ of various analytical instruments.The purpose of this study was to develop a PK model that describes the plasma concentration profiles under LLOQ of HPLC using urinary and biliary excretion data, and we used pyrrole (Py)-imidazole (Im) polyamides as model compounds. MATERIALS AND METHODS Chemicals and ReagentsThe Py-Im polyamides 1035 and 1666 reported previously 4) were purchased from Gentier Biosystems Co., Ltd. (Kyoto, Japan). Py-Im polyamide 1035 is composed of Ac-ImPyPy-g-ImPyPy-b-Dp (b: b-alanine, Dp: N,N-dimethylaminopropylamine, g: g-butyric acid), and Py-Im polyamide 1666, with a higher molecular weight, is composed of Ac-PyPy-b-PyImPy-g-PyPyPy-b-ImPy-b-Dp. The molecular weights of Py-Im polyamides 1035 and 1666 calculated on the basis of standard atomic weights 5) are 1035.12 and 1665.78, respectively. HPLC-grade methanol, acetonitrile, and distilled water were purchased from Kanto Chemical Co., Inc. (Tokyo, Japan). Midazolam and all other reagents of the highest quality were purchased from Wako Pure Chemical Industries, Ltd. (Tokyo, Japan). Pooled rat liver microsomes, pooled human liver microsomes, reduced nicotinamide adenine dinucleotide phosphate (NADPH) regenerating system solution, 1Ј-hydroxymidazolam, and 4-hydroxymidazolam were purchased from BD Bioscience (Woburn, MA, U.S.A.).Analysis of Py-Im Polyamides Unchanged Py-Im polyamides 1035 and 1666 were extracted from rat urine and bile by solid-phase extraction using Oasis ® WCX and MAX cartridges with both reverse-phase and ion-exchange sorbents. The HPLC method was based on a previous report with minor modification.4) The quantitative analyses of PyIm polyamides 1035 and 1666 including the preparation procedure have been validated using the criteria of the Food and The use of urinary and/or biliary excretion data was considered as an alternative approach if the bioanalytical method lacked the appropriate sensi...

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The pharmacokinetics of pyrrole (Py)-imidazole (Im) polyamides was studied in rats after the intravenous administration of these compounds. Py-Im polyamide (A) was composed of Ac-ImPyPy-ImPyPy-beta-Dp (beta: beta-alanine, Dp: N,N-dimethylaminopropylamide). Py-Im polyamide (B) was composed of Ac-PyIm-beta-ImIm-PyPy-beta-PyPy-beta-Dp. Py-Im polyamide (C) was composed of Ac-PyPy-beta-PyImPy-PyPyPy-beta-ImPy-beta-Dp. The molecular weight of Py-Im polyamide (A) was 1035.12, that of Py-Im polyamide (B) was 1422.51 and that of Py-Im polyamide (C) was 1665.78. After the intravenous injection of Py-Im polyamide (A) at 1.3, 2.0, 7.5 and 15.0 mg/kg, Py-Im polyamides (B) and (C) at 1.0, 2.0, 3.0 and 5.0 mg/kg, the average systemic clearance and the volume of distribution at the steady state obtained by a non-compartmental method were in the ranges of 4.6-6.4 ml/min/kg and 244-412 ml/kg, 8.9-10.3 ml/min/kg and 1990-4567 ml/kg, and 7.3-11.9 ml/min/kg and 407-667 ml/kg, respectively. Dose linearity of Py-Im polyamides was observed. The plasma concentration-time profiles after the intravenous administration of Py-Im polyamides (A) and (B) were fitted well by a two-compartment model. Py-Im polyamide (C) was observed at high concentrations in the lungs. The plasma concentration-time profiles after the intravenous administration of Py-Im polyamide (C) were described using a catenary two-compartment model. This model is useful for describing the time course after the administration of high-molecular-weight Py-Im polyamides.

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Here, the mannose‐rich yeast binding activity of immobilized Con A was tested when the beads were stored for up to 60 days in a freezer (‐20 C), a refrigerator (4C), and at room temperature (24C), compared with controls stored in a refrigerator under the manufacturer's specifications. In about a total of 9,000 replicate experiments, beads stored at the 3 temperatures studied, maintained their ability to effectively bind yeast (Saccharomyces cerevisiae) over the 60 day period. Linear trend lines for the 3 storage temperature graphs confirmed that the room temperature condition was slightly better than the refrigerator condition, that was slightly better than the freezer condition. The difference between the trend lines was at their widest divergence about 12%. While the beads bound yeast effectively after being stored at the temperatures tested, the experiments were conducted at 24C. It is likely that if the actual experiments were done at different temperatures, the kinetics of yeast binding to the beads would be affected by temperature. This issue was not examined in this study but should be investigated, as many experiments in a wide variety of systems might require being conducted at different temperatures. This is a model system for studying the efficacy of potential glycan‐based anti‐infection drugs (Supported by NIH NIGMS SCORE (S0648680), MARC, RISE, the Joseph Drown Foundation and the Sidney Stern Memorial Trust).