Magnetic resonance spectroscopy for measuring the biodistribution and in situ in vivo pharmacokinetics of fluorinated compounds: validation using an investigation of liver and heart disposition of tecastemizole.
Magnetic resonance spectroscopy for measuring the biodistribution and in situ in vivo pharmacokinetics of fluorinated compounds: validation using an investigation of liver and heart disposition of tecastemizole.
复制标题
用于测量氟化化合物的生物分布和原位体内药代动力学的磁共振波谱：通过研究替卡司咪唑的肝脏和心脏分布进行验证。
DOI：
10.1111/j.1365-2710.2006.00735.x
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发表时间：
2006
影响因子：
2
通讯作者：
Renshaw,PF
中科院分区：
文献类型：
--
作者：
Schneider,E;Bolo,NR;Frederick,B;Wilkinson,S;Hirashima,F;Nassar,L;Lyoo,IK;Koch,P;Jones,S;Hwang,J;Sung,Y;Villafuerte,RA;Maier,G;Hsu,R;Hashoian,R;Renshaw,PF
Background and objective:The study of biodistribution andin situpharmacokinetics is a challenging, but sometimes very important, aspect of premarketing characterization of drugs. We aimed to develop a non‐invasive fluorine magnetic resonance (MR) spectroscopic method for the absolute quantitation of a mono‐fluorinated compound and of its metabolites in the heart and liver of healthy subjects for this purpose.Method:We used fluorine MR spectroscopy (MRS) at 4 T (Tesla) and external standardization in an open label multiple‐dose study. Twenty‐three healthy adult subjects were enrolled in the study. The surface coil localized fluorine MR spectrum was monitored in the heart and liver at baseline and after oral administration of multiple doses of tecastemizole. Steady‐state measurements were made at set time points that depended upon dose, and washout measurements were made only on subjects in whichin vivofluorine signal was observed.Results and discussion:At 4 T, under the given experimental conditions, the method had a lower limit of quantitation (LLOQ) of about 2·6μmand a limit of detection (LOD) of about 0·3μmfor solution state samples (linewidth approximately 15 Hz). The measurement reproducibility was 6·4% using a 50μmphantom. The effect of MR operator and spectral analyst on the calculated calibration curve slope was small, with inter‐rater correlation coefficients of 0·999 and 0·998 respectively. MR signal from fluorine‐containing tecastemizole‐related moieties was observedin situonly at day 8 in the liver of three of five subjects dosed at 270 mg/day. The averagein situconcentration was estimated to be 58 ± 22μm, with an average test–retest reproducibility of 216%. Extrapolating thein vitroresults to human measurements, with an approximate linewidth of 250 Hz, predictsin situLOD and LLOQ values of approximately 6 and 44μmrespectively. However, the human study had a fluorine MRS LOD of approximately 20μm. The decrease in sensitivity and the increase in variability of thein vivo,in situmeasurements compared with the validation study most likely arose from coil placement and incomplete rephasing of the MR signal by the respiratory phase compensation method.Conclusion:The measured concentrations were the lowest ever recorded for a multi‐dose exogenous mono‐fluorinated compound in the human liver using a validated fluorine MR quantitation method. The proposed non‐invasive MR method for studying the biodistribution andin situpharmacokinetics of mono‐fluorinated compounds in the liver and heart should have broader application to the development of non‐invasive biomarkers.
