Rüdiger Port

Pharmacokinetic Parameters in Cns Gd-dtpa Enhanced Mr Imaging

Dynamic MR imaging can be used to study tissue perfusion and vascular permeability. In the present article a procedure for dynamic MR is presented, which (a) accurately resolves the fast kinetics of tissue response during and after intravenous infusion of the paramagnetic contrast medium Gd-DTPA and (b) yields a linear relationship between the measured MR signal and the Gd-DTPA concentration in the tissue. According to these features, the measured signal-time curves can be analyzed within the framework of pharmacokinetic modeling. Tissue response has been parameterized using a linear two-compartment open model, with only negligible effects of the peripheral compartment on the central compartment. The three model parameters were fitted to the signal-time data pixel by pixel, based on a set of 64 rapid SE images (SE 100/10 ms, image scan time 13 s, interscan intervals 11 s). This makes it possible to construct parameter images, whereby structures become visible that cannot be distinguished in conventional Gd-DTPA enhanced MR. As a clinical example, the approach is discussed in a case of glioblastoma.

Noninvasive determination of the arterial input function of an anticancer drug from dynamic PET scans using the population approach

For the application of a kinetic model to PET data, it is generally necessary to obtain the arterial input function (AIF). It was the aim of the present study to introduce a method suitable for the determination of the AIF of a substance that undergoes biochemical transformation from noisy PET data: the population approach. F-18 labeled 5-fluorouracil (5-[18F]FU) was administered i.v. to eight patients suffering from liver metastases of colorectal carcinoma. Radioactivity concentrations in liver and aorta were dynamically measured with PET over 120 min. Pharmacokinetic analysis was carried out by applying a five-compartment model to individual activity-time data for the eight patients or to the mean activity-time data among the eight patients. The mean values of all parameters describing 5-FU transport and catabolism, i.e., volumes of distribution and clearances, as well as interindividual coefficients of variation (CV) were calculated according to both approaches. With our model, we were able to separate the concentration-time course of 5-FU in plasma, i.e., the AIF, from that of its major catabolite alpha-fluoro-beta-alanine (FBAL). As far as the mean parameter estimates are concerned, the differences between both approaches are not significant. For the liver data, the CVs are almost the same for both approaches. For the parameters concerning the aorta, however, there is a decrease in the CVs by using the population approach. For example, the CV of the central distribution volume of 5-FU was 30% for the individual approach and 18% for the population approach. With the population approach, it is possible to determine the AIF of drugs that undergo metabolic conversion, such as anticancer drugs, from the abdominal aorta visualized on PET images. The population approach helps to overcome noise in individual data. Since no measurements are needed in addition to the PET examination, the suggested method helps to reduce risk and pain for the patients as well as cost and thus facilitates large scale patient studies.

Kinetic modeling of in vivo—nuclear magnetic resonance spectroscopy data: 5–Fluorouracil in liver and liver tumors

Kinetic modeling has been applied to the time course of the nuclear magnetic resonance signal intensities of 5‐fluorouracil and the sum of its catabolites, α‐fluoro‐β‐ureido propanoic acid and α‐fluoro‐β‐alanine, as monitored in liver tumors of seven patients with cancer after brief intraarterial infusion of 5‐fluorouracil. Because these data represent only relative tissue concentrations, only ratios of clearance and volume parameters can be estimated (e.g., clearance/central volume of distribution or central volume of distribution/steady‐state volume of distribution). On the other hand, parameters that do not refer to volumes, such as half‐lives or maximal velocity of metabolic conversion of a nonlinear model, can be estimated in absolute terms. A nonlinear three‐compartment model gave satisfactory fits with all of the individual data sets. Kinetics of 5‐fluorouracil and catabolites were similar in five patients with metastases of colorectal adenocarcinomas but differed from those of two patients with cholangiocarcinoma and metastases of an anaplastic carcinoma of unknown origin, respectively.

Pharmacokinetics and whole-body distribution of the new chemotherapeutic agent β-D-glucosylisophosphoramide mustard and its effects on the incorporation of [methyl-3H]-thymidine in various tissues of the rat

Abstract β-D-Glucosylisophosphoramide mustard (β-DGlc-IPM) is a new, potential chemotherapeutic agent currently under investigation. Its pharmacokinetics in plasma and elimination of the parent drug and its metabolites via urine, bile, and exhaled air were studied in female Sprague-Dawley rats after bolus injection of 315 mg/kg. Typically, the drug’s disposition from plasma follows a linear two-compartment model with half-lives (t1/2) of 1.8 (t1/2α) and 32 min (t1/2β). The rate of clearance is 0.0046 (range 0.0030–0.0071) l min-1 kg-1, and the steady-state volume of distribution (Vss) is 0.18 (0.08–0.042) l/kg (mean±interindividual standard deviation). In human plasma, 28.1±2.6% (mean±SD) of the drug (concentration range 0.5–5 mg/ml) is bound to plasma proteins (predominantly to albumin). Biliary excretion of the parent drug accounts for 2.9±1.7% of the dose; its elimination in the form of 14CO2 via exhaled air is less than 1%. Within 24 h, 63.5±4.9% of the 14C-labeled drug is excreted unchanged in the urine, whereas 17.5±5.1% is excreted in the urine as metabolites. In addition, β-D-Glc-[14C]-IPM was given as a bolus injection to female Sprague-Dawley rats at dose levels of 315 and 56.2 mg/kg. The distribution of radioactivity into tissue was examined qualitatively by whole-body autoradiography (WBA). Parallel experiments were carried out using the high dose of the L-derivative. After dosing with the D-compound, the highest levels of radioactivity were found in the liver, kidneys, thymus, thyroid gland, and central nervous system, including the brain. A similar distribution pattern was observed for the L-compound, except in the brain, which contained negligible levels of radioactivity. The distribution of the D-compound (high dose) was also investigated in male Copenhagen rats bearing a Dunning prostate tumor. The results were similar to those obtained in healthy Sprague-Dawley rats. Additionally, radioactivity was found in the tumor at 1 h after dosing with the drug and remained there even after 24 h. The effects of β-D-Glc-IPM on the incorporation of [methyl-3H]-thymidine into the DNA of the liver, kidneys, thymus, spleen, esophagus, and bone marrow of the rat were examined following tissue excision and liquid scintillation counting at 2, 8, and 24 h after administration of the drug. β-D-Glc-IPM showed no effect on the incorporation of [methyl-3H]-thymidine in the liver and an insignificant reduction in kidney DNA (maximal reduction: −27.3%). However, after 8 h there was a marked reduction in the incorporation rate in the thymus (−83.7%), spleen (−74.6%), and esophagus (−87.2%), with a tendency toward recovery within 24 h. In bone marrow cells a reduction of −75.5% (8 h) and −73.3% (24 h) was observed.

Some Examples of Dose-Response Studies in Chemical Carcinogenesis

Three studies of DRUCKREY and his group, on diethylnitrosamine and 4-dimethylaminostilbene, are described. In a recent experiment, urethane was given chronically to rats and mice, at doses between 100 and 12,500 mug/kg/day. The results in rats were evaluated with the Mantel-Bryan procedure; risk estimates greatly differed, depending on the slope used for calculation.

PHARMACOKINETICS OF 5-FLUOROURACIL AFTER SHORT SYSTEMIC INFUSION : PLASMA LEVEL AT THE END OF THE DISTRIBUTION PHASE AS AN INDICATOR OF THE TOTAL AREA UNDER THE PLASMA CONCENTRATION-TIME CURVE

Summary: The correlation between single plasma concentration (CP) values of 5-fluorouracil (FU) after a 10-minute i.v. infusion and the total area under the plasma concentration-time curve (AUC) has been studied in 26 cancer patients. FU dose was either 320–550 mg/m2 (seven patients, 13 treatments) or 610–960 mg/m2 (19 patients, 30 treatments). Linear single CP-AUC relationships were found in both dose groups with the CPs at 1, 5, 10, 15, and 30 minutes after the end of infusion. Parameters of linear regression of AUC on single CP differed between the two dose groups. For the high-dose group, the single CPs at repeated treatments were tested as estimators of the total AUC at these treatments, using calibration lines relating total AUC to single CP, which were derived from the data of the first (or only) treatments of all patients. The “best” AUC estimators of the total AUC were the CPs at 10 and 15 minutes after the end of infusion, with a bias of only 2% and an imprecision of only 11% of the AUC values directly determined from the complete concentration-time profiles of the repeated treatments. Because of the close correlation between these single CPs and the total AUC, these CPs should be considered equivalent to the AUC as an overall index of individual FU kinetics after brief infusion of high doses.

The effect of methotrexate pretreatment on 5-fluorouracil kinetics in sarcoma 180 in vivo

Synergy of sequential MTX and 5-FU has been shown in several in vitro and in vivo systems. In the present study the influence of time interval between MTX and 5-FU and MTX dose on 5-FU accumulation in tumor cells has been examined in Sarcoma 180 in vivo. There was a clear relationship between MTX dose applied and amount of 5-FU detected in the acid-soluble fraction, the RNA fraction and the thymidylate synthase complex fraction. Also, the MTX-5-FU time interval affected clearly the amount of 5-FU detected in all three fractions, the optimum time interval being 8-12 hr. The results indicate that for sequential application of MTX and 5-FU selection of an adequate MTX dose and a sufficient time interval is crucial to achieve synergistic action.

Influence of Tetrachlorodecaoxide (Ryoxon®) on the Development of Leukemia after Total-Body Gamma-Irradiation

The effect of tetrachlorodecaoxide (TCDO) treatment after total-body irradiation (TBI) with gamma-rays (single dose, about LD 50) on the development of radiation-induced leukemia was tested in rats. TCDO was applied intravenously from day 4 through day 11. The control group was exposed to the same dosage of X-rays (TBI), but received physiological saline solution instead of TCDO. Compared to the control group, TCDO therapy initially markedly increased the survival rate: 72 versus 44% (6 months after TBI) and 36 versus 20% (1-year survival rate). The overall survival, however, was not significantly prolonged. TBI caused leukemia in 36% of the rats in the irradiation control group without TCDO treatment, however, none of 24 rats treated with TCDO after X-ray exposure developed leukemia. Since in this study TCDO was only administered for 8 days during the acute phase of radiation syndrome, we suppose that additional TCDO treatment at various times later on would lead to even better results.

Pharmakokinetische Analyse des MRT-Signalverlaufs vor, während und nach i.v. Gd-DTPA-Infusion

Zusammenfassung Wird fur die dynamische Magnet-Resonanz-Tomographie (MRT) eine Spin-Echo-Sequenz mit einer kurzen Repetitions- und Echozeit verwendet (z.B. SE 100/10 ms), so ist der Signalanstieg nach i.v. Gd-DTPA-Applikation linear mit der lokalen Gd-DTPA-Konzentration im Gewebe verknupft. Die gemessenen Signal-Zeit-Verlaufe konnen daher als Konzentrations-Zeit-Verlaufe interpretiert werden, wodurch sich die Moglichkeit eroffnet, den Signalverlauf wahrend und nach i.v. Gd-DTPA-Infusion mit Hilfe eines geeigneten pharmakokinetischen Modells mathematisch zu beschreiben. In unserer Studie konnten die gemessenen Signal-Zeit-Verlaufe adaquat mit Hilfe eines offenen Zwei-Kompartiment-Modells parametrisiert werden.

Research on Diagnosis and Therapy

In the battle against cancer, diagnosis has a crucial strategic significance. Diagnostic shortcomings will be difficult to counteract by therapy.