A Method to Quantitatively Measure Transcapillary Transport of Iodinated Compounds in Canine Brain Tumors with Computed Tomography

We present a quantitative method for determining a blood-to-tissue influx constant ( K1), a tissue-to-blood efflux constant ( k2), and tissue plasma vascular space ( Vp) that uses a computed tomographic (CT) scanner to make tissue and plasma measurements of the concentration of an iodinated compound. Meglumine iothalamate was infused intravenously over time periods of 0.5–5 min, up to 49 CT scans were obtained at one brain level, and arterial plasma was sampled over a 30- to 40-min period. K1, k2, and Vp were calculated for each voxel of the 320 × 320 matrix, using a two-compartment pharmacokinetic model and nonlinear least-squares regression. The method was used in dogs with avian sarcoma virus–induced brain tumors. As many as four studies on different days were done in the same animal. In tumor-free cortex, K1 of meglumine iothalamate was 2.4 ± 1.7 μl g−1 min−1 (mean ± SD) and Vp was 3.4 ± 0.5 ml 100 g−1. Mean whole-brain tumor K1 values ranged from 3.3 to 97.9 μl g−1 min−1; k2 ranged from 0.032 to 0.27 min−1; and Vp ranged from 1.1 to 11.4 ml 100 g−1. These values were reproducible in serial experiments in single animals. Independent verification of K1 values was obtained with quantitative autoradiographic measurements of α-aminoisobutyric acid, which has similar physicochemical properties to meglumine iothalamate. The CT methodology is capable of demonstrating regional variation of trans-capillary transport in brain tumors and may be of value in the study of human brain tumors.

Effect of hyperosmotic blood-brain barrier disruption on transcapillary transport in canine brain tumors

✓ Whether hyperosmotic blood-brain barrier (BBB) disruption is a technique that can be used to increase permeability of brain-tumor capillaries and thereby transiently increase drug delivery to the brain tumor is controversial. Nine virally induced brain tumors were studied in seven dogs, before and after hyperosmotic BBB disruption with 1.4 osmolar mannitol. Each dog was studied with computerized tomography (CT) after administration of the water-soluble tracer meglumine iothalamate. Each study lasted 30 minutes. A baseline CT scan and 35 to 40 additional CT scans were obtained to provide a time-related measurement of the amount of meglumine iothalamate in tissue (Am(t)), and 30 plasma samples were collected to provide the time-related measurement of meglumine iothalamate in plasma (Cp(t)). The data were analyzed by three different methods: 1) a two-compartment model and nonlinear curve fitting were used to calculate K1 (blood-to-tissue or influx constant), k2 (tissue-to-blood or efflux constant), and Vp (plasma vascular space); 2) K1 values were calculated with a two-compartment model, assuming no efflux, at the time point for each CT scan; and 3) a “tissue advantage ratio” was calculated that expressed the ratio of tissue uptake of meglumine iothalamate at each time point, comparing values before and after BBB disruption. Regardless of which method of data analysis was used, there was a marked and significant increase in transcapillary transport of meglumine iothalamate to tumor-free brain regions, while there was only a small, transient, and insignificant increase to the brain tumors. Although there were often marked increases in delivery to cortex in the same hemisphere as the tumors, there was no significant increase to brain immediately surrounding the tumors, perhaps due to altered circulatory dynamics in this region. These data raise serious questions as to the wisdom of using this technique to increase drug delivery to brain tumors in patients and strongly support the continued study of this technique in experimental brain tumors before it is used in patients.

Iohexol and Meglumine Iothalamate in Shoulder Arthrography

The first clinical experience with the new contrast medium, iohexol, in shoulder arthrography is reported. A double-blind comparison of iohexol and meglumine iothalamate, a conventional medium in standard use for arthrography, was carried out in a consecutive series of 60 adult patients forming two groups of 30 subjects each. No difference in the radiographic quality was seen immediately after contrast injection but in exposures at 20 min iohexol gave a significantly better arthrographic quality. Practically no adverse effects occurred during the examinations. Although minor side effects were numerous in both groups during the two days following arthrography, they were somewhat more frequent in patients given iothalamate