Localized COSY and DQF-COSY 1H-MRS sequences for investigating human tibial bone marrow in vivo and initial application to patients with acute leukemia.

PURPOSE: To develop 2D 1H-MRS measurement sequences for the evaluation of bone marrow lipids, and to assess these measurement sequences in healthy and diseased bone marrow. MATERIALS AND METHODS: Single-voxel localized variants of COSY and DQF-COSY 2D 1H-MRS sequences were developed for use at 1.5 T to investigate the biochemical composition of human bone marrow in vivo. The performance of each sequence was initially tested in vitro using lipid phantoms. An unsaturated lipid proton index was developed to interrogate the degree of unsaturation within the triacylglyceride (TAG) acyl chains. Localized 2D 1H-MRS data were obtained from the bone marrow of healthy controls (N = 6), patients presenting with acute leukemia (N = 6) and patients with acute leukemia in remission (N = 4). RESULTS: The COSY and DQF-COSY data recorded from all subject cohorts were similar, and the unsaturated lipid proton index did not reveal significant differences between patient groups. Variations in water content and measured relaxation times showed minor differences between the measurement groups. CONCLUSIONS: No significant differences were observed in the spectra obtained from bone marrow using the 2D 1H-MRS sequences. A novel unsaturated lipid proton index was developed.

Identification of biliary metabolites of ifosfamide using 31P magnetic resonance spectroscopy and mass spectrometry.

Biliary excretion is a significant component in the metabolism of many drugs, but remains difficult to detect and characterise non-invasively. A previous publication recently described the detection of metabolites of ifosfamide in gall bladder in a guinea pig model using in vivo 1H-decoupled 31P 3-D magnetic resonance spectroscopic imaging and a clinical 1.5 T MR scanner.. Here high-resolution 31P magnetic resonance spectroscopy (MRS) of extracted bile identifies peaks as parent ifosfamide (1.19+/-1.47 mM; mean+/-sd), carboxyifosfamide (2.04+/-1.04 mM) and a major contribution from a previously unreported peak at 16.0 ppm (4.05+/-2.38 mM). The unknown resonance was identified using liquid chromatography-mass spectrometry (LCMS) as the glutathione conjugate of ifosfamide (MW=531). This was confirmed by analysing products from the reaction of glutathione with ifosfamide using LCMS and MRS. These results demonstrate how combined in vivo and analytical MRS, together with mass spectrometry, can help identify visceral routes of drug metabolism, thereby aiding understanding of +/-drug disposition and mechanisms of action and toxicity. In particular, the distribution of ifosfamide and its metabolites into bile may be related to oxazophosphorine-related cholecystitis reported in patients.

Quantitative assessment of the hepatic pharmacokinetics of the antimicrobial sitafloxacin in humans using in vivoF magnetic resonance spectroscopy.

AIMS: To measure hepatic concentrations of the fluorine-containing antimicrobial, sitafloxacin, using in vivo(19)F magnetic resonance spectroscopy (MRS). METHODS: Data were acquired from eight healthy subjects at 2, 5, 8 and 24 h following doses of 500 mg day(-1) for 5 days using a (1)H/(19)F surface coil in a 1.5T clinical MR system. Tissue water was used as a reference. RESULTS: Estimated liver concentrations at 2 h were 15.0 +/- 4.0 microg ml(-1) (mean +/- 95% CI), compared with 3.54 +/- 0.58 microg ml(-1) in plasma (n = 6), and fell below threshold concentrations (2 microg ml(-1)) by 24 h. CONCLUSIONS: (19)F MRS is able to detect and quantify sitafloxacin in the liver. There was no evidence for the hepatic retention of the drug.

Human gallbladder bile: noninvasive investigation in vivo with single-voxel 1H MR spectroscopy.

Proton (hydrogen 1) magnetic resonance (MR) spectroscopy was used to study model and porcine bile in vitro. The method was subsequently developed to facilitate the acquisition of in vivo 1H MR spectra from the gallbladder bile of 10 human volunteers. Signals attributable to phosphotidylcholine and conjugated bile acid protons were observed in eight of the 10 volunteers. Phosphotidylcholine concentrations were estimated, and five values (mean = 35.8 mmol/L, SD = 9.8) were within the expected range of levels in human bile. Findings in this preliminary investigation indicate that human gallbladder bile can be qualitatively and quantitatively studied noninvasively with 1H MR spectroscopy.

Ifosfamide pharmacokinetics and hepatobiliary uptake in vivo investigated using single- and double-resonance 31P MRS.

MRS has considerable potential for the measurement of drug pharmacokinetics in vivo. In this study single- and double-resonance (31)P MRS was used to investigate the biodistribution, pharmacokinetics, and metabolism of ifosfamide following administration of 500 mg/kg ifosfamide in guinea pigs. (1)H-decoupling was found to nearly double the signal of detected peaks. However, in contrast to studies of ifosfamide in solution, the polarization transfer sequence gave no further signal enhancements. This was attributed to significantly reduced relaxation times in vivo. Chemical shift imaging (CSI) measurements showed that significant proportions of ifosfamide-related (31)P MRS signals arose from the liver, as expected, but also from the gall bladder, which was not predicted from the current literature. Signals were observed within 5 min of the end of administration. The halflife in liver was approximately 74 min, whereas in gall bladder there was no measurable signal decay during the 2.5-hr studies. High-resolution (31)P MRS of bile showed that the "ifosfamide" peak in vivo consists of at least two compounds. The lower-concentration peak is ifosfamide, and an investigation is under way to identify the higher-concentration peak. Other peaks observed in bile are tentatively assigned to carboxy-ifosfamide and dechloroethyl-ifosfamide. Overall, (1)H-decoupled (31)P MRS has proved to be a useful tool for investigating the metabolism of ifosfamide in vivo.

The effect of Gd-DTPA on T(1)-weighted choline signal in human brain tumours.

The influence of Gd-DTPA on T(1)-weighted (T(1)W) proton MR spectra has been investigated in 19 patients with histologically verified low (n = 13) or high-grade (n = 6) gliomas. Repeat measurements were performed on 9 patients (7 low-grade and 2 high-grade), with 28 examinations performed in total. Comparison of spectra obtained before and after 0.2 mmol/kg Gd-DTPA showed contrast agent induced broadening of the choline signal without significant signal area change. Lack of enhancement of the choline signal with the T(1)-weighted acquisitions implies that the contrast agent and the trimethylamine-containing species do not undergo significant direct interaction. Contrast agent induced changes in the choline signal observed in this and previous studies may, therefore, be attributable to T2*/susceptibility-based effects.