pharmacokinetic analysis of blood distribution of intravenously administered 153gd-labeled...

Magneric Resonance Imagmg, Vol. 8, pp. 567-575, 1990 Printed in the USA. All rights reserved.

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l Original Contribution

PHARMACOKINETIC ANALYSIS OF BLOOD DISTRIBUTION OF INTRAVENOUSLY ADMINISTERED ‘53Gd-LABELED

Gd(DTPA)2- AND 99MT~(DTPA) IN RATS

P. WEDEKING, S. EATON, D.G. COVELL,* S. NAIR, M.F. TWEEDLE,

AND W.C. ECKELMAN

The Squibb Institute for Medical Research, New Brunswick, New Jersey 08903, *Laboratory of Mathematical Biology, DCBD, National Institutes of Health, National Cancer Institute, Frederick, Maryland 21701-1013, USA

Rat plasma distribution data obtained following IV administration of 99mTc(DTPA) alone or after co- administration of WmTc(DTPA) and Ls3Gd-labeled Gd(DTPA)*- at 0.001, 0.1, and 1.0 mmol Gd/kg were evaluated using compartmental modeling techniques. A three-compartment open model was found to fit the data significantly better (P < 0.01) than a two- or four-compartment open model. This model incorporates and links the plasma and urine data and includes a delay to account for the transit time through the kidneys/ureters. The two nonplasma compartments of the model were assumed to be related to rapidly and slowly equilibrating tissues. Tc(DTPA) and Gd(DTPA)2- had nearly identical pharmacokinetic profiles in plasma and the rate constants were essentially the same. No significant dose dependent pharmacokinetic differences were found for the range of Gd(DTPA)‘- doses tested. Simulations of the proposed three-compartment model were used to generate concentration-time curves for each of the three compartments.

Keywords: Pharmacokinetics; Gd(DTPA); Contrast agents.

INTRODUCTION

Time-dependent plasma distribution data obtained from rats following intravenous administration of technetium-99m diethylenetriaminepentaacetic acid, 99mTc(DTPA), a radiodiagnostic agent used to evaluate glomerular filtration, 11~24*25 indicate that there is a rapid distribution of the complex into nonplasma spaces. I7 Analysis of distribution data obtained from dogs3’ and rats3’ following intravenous administration of gadolinium-diethylenetriaminepentaacetic acid, Gd(DTPA)2-, a magnetic resonance imaging (MRI) contrast agent that also has rapid distribution into nonplasma spaces, shows that its plasma disappearance and excretion profiles are very similar to those obtained for Tc(DTPA). 21 Pharmacokinetic analyses of plasma distribution data using traditional best-fit linear analysis techniques suggest that the published data can be described by a two-compartment open pharmacokinetic model”; one compartment is assumed to be the site of injection into plasma, and the

second compartment is assumed to be related to the interstitial space.31

The pharmacokinetic analysis computer program

SAAM has been under development since 1959.4 More recently an interactive version of SAAM29, called CONSAM, has been created that can be used for pharmacokinetic data analyses. lo CONSAM can be used to perform compartmental analyses of time- dependent data (such as plasma concentration-time data) using standard methods of compartmental analysis. Model fits to the data are monitored by reduced Weighted Sum of Squared residuals (WSS).9 Utilizing an F-statistic developed by Boxenbaum et al.,’ the WSS values of two models can be compared to determine whether there is a statistically significant improvement in the fit by adding or subtracting a compartment in the proposed model.

Our goal was to define a multi-compartment pharmacokinetic model that best described our time-dependent plasma concentration and urine data. Although the pharmacokinetics of i.v. administered 99mT~-

RECENED 12/11/89; ACCEPTED 3/13/90. Institute for Medical Research, New Brunswick, NJ 08903, Address correspondence to M.F. Tweedle, The Squibb USA.

567

568 Magnetic Resonance Imaging 0 Volume 8, Number 5, 1990

(DTPA) have been evaluated extensively, 1 1*17 the pharmacokinetics of Gd(DTPA)2- remain under ac- tive investigation. The aims of this study are (i) To determine and evaluate the plasma distribution and urinary excretion of co-administered 99mT~(DTPA) and 153Gd-labeled Gd(DTPA)2- during the first few min following intravenous injection, (ii) to determine if the distribution/pharmacokinetic profile is affected by increasing doses of Gd(DTPA)2-; and (iii) to develop a compartmental model that can be used to describe the kinetics of plasma-to-tissue distribution for these complexes. 99mT~(DTPA) and 153Gd-Gd(DTPA)2- were co-administered so that paired statistics could be used in the analysis.

EXPERIMENTAL

Preparation of Complexes and Doses 99mTc(DTPA) was prepared by reconstituting a

Techneplexo kit with 5 mL of 99mTc-generator (Mini- tee Generator@) eluate (0.9% saline) containing -0.4 mCi of 99mT~ pertechnetate. Radiochemical purity (RCP) of the 99mTc(DTPA) was determined via as- cending paper chromatography (Whatman No. 1) in 0.9% NaCl solution. A kit was prepared for each day’s experiments and all injections of 99”Tc(DTPA) were made within 6 hr of kit preparation. RCP determinations indicated labeling efficiency was 96.9- 98.5070 .23*25 The radioconcentration at the time of preparation was -80 uCi 99mTc/mL.

Gd(DTPA)2- was prepared by mixing Gd203 with a slight excess of DTPA ligand (purchased from Alfa Products, Danvers, MA) and heating with agitation at 90” C for 5 hr at pH <213; after the chelate was formed, the pH was adjusted to 7.3 with 1 M NaOH. Radiolabeled Gd(DTPA)2- was prepared by mixing Gd(acetate),, DTPA ligand, and 153GdC13 in water and heating with agitation at 90” C for approximately 30 min at pH <2; the pH was then adjusted to 7.3 with 1 M NaOH.

Chemical purity (>99%) was determined by reversed-phase HPLC with fluorescence detection. l3 RCP of the 153Gd(DTPA)2- was determined by silica gel ITLC. 27 The maximum level of free 153Gd3+, at the upper 95% confidence level in the 153Gd(DTPA)2-, was <0.2%. 153Gd(DTPA)2- was combined with un- labeled Gd(DTPA)2- to obtain 153Gd-Gd(DTPA)2-. 153Gd-Gd(DTPA)2- was prepared at three chelate concentrations and injected at three dose levels.

HPLC was used to verify that solutions containing Gd(DTPA)2- and 99mTc(DTPA) were stable to loss of metal or chemical transformation in vitro over a period of 4 hr at pH 7. In a separate study using rats,

not reported here, HPLC analysis verified that Gd(DTPA)2- excreted with the urine is in the same chemical form (same HPLC retention times) as the injected material.

In the first study (Study l), 1 .O mL of 99mTc(DTPA) was combined with 1 .O mL from one of the three solutions of 153Gd-Gd(DTPA)2- and the prescribed al- iquot of the mixture transferred into an injection syringe for immediate injection. The remaining mixture was reserved to prepare appropriate radioassay standards. The volume injected was 2 mL of the mixture/kg body weight. This resulted in 99mTc(DTPA) being administered at -40-80 uCi 99mTc(DTPA)/kg, and 153Gd-Gd(DTPA)2- being administered at 10 uCi lS3Gd/kg and 0.001, 0.1, or 1 .O mmol Gd(DTPA)2-/kg.

A control group (Study 2) received only 99mT~- (DTPA). Data from this group was used to determine the effects of co-injection with 153Gd(DTPA)2- on the plasma distribution/pharmacokinetic profile of 99mTc(DTPA). The injected volume was 1 mL/kg body weight in this group.

In Vivo Protocol Male Sprague-Dawley-derived rats (Charles River

Laboratories, Inc., Wilmington, MA) weighing 375 + 30 g were used. Each rat was anesthetized with 100 mg ketamine HCl/kg, i.p. ‘; maintenance doses were administered, i.p., as needed. The right femoral vein was exposed for injection. The left carotid artery was iso- lated and cannulated with a lo-cm section of PE 50 polyethylene tubing.

Each dose group in Study 1 contained six rats. Each rat was injected with the prescribed dose- mixture combination via the femoral vein at a rate of 0.1 cc/l .5-2 sec. The six rats in Study 2 were injected with 99mTc(DTPA) at this same rate.

Beginning 60 set postinjection, lo-UL aliquots of blood were serially collected from the carotid artery cannula directly into precalibrated capillary tubes; the filled capillary tubes were placed in suitable counting tubes. Blood samples used in the analyses were taken at 30-set intervals up to 4 min, 60-set intervals from 4-10 min, and thereafter at 15, 20, 30, 40, 50, 60, 75, and 90 min. Care was taken to flush residual blood from the cannula just prior to obtaining the samples. Less than 1 mL of blood (<5% of the rat’s blood volume) was taken from each rat during the procedure. Approximately 2-3 mL of 0.9% NaCl solution was administered during the experiment to each rat via the carotid artery cannula to flush and maintain cannula patency.

Rats were sacrificed by injecting an euthanasia solution into the carotid artery. The bladder and urine

Pharmacokinetic analysis of blood distribution in rats 0 P. WEDEKING ET AL. 569

were removed immediately after sacrifice and trans- Table 1. Average rate constants for movement of

ferred to a counting tube. complexes between compartments

The sample tubes, along with appropriate standards to compensate for counting geometry,were as- sayed in an automatic gamma counter with a fixed energy window (So-120 KeV); both 153Gd (97 and 103 KeV; half-life = 242 days) and 99mT~ (140 KeV; half- life = 6 hr) were counted at this setting. Each sample was counted for 1 min on the day it was collected. For the samples that contained 2 radionuclides (Study l), the tubes were counted a second time for 2 min, four days later, allowing sufficient time for the decay of 99mTc. The first counting included both radionu- elides; the second counting contained only 153Gd and was used to determine the 99mT~ content in the first counting.

Rate constant (min-‘) (SD)

UXY) 99mT~ 153Gd

The % Injected Dose (ID)/g-blood for each complex was obtained directly from the blood data. A mean time-dependent blood distribution for each complex was determined by calculating the mean % ID in the blood pool at each sampling time by using a blood volume factor of 58 mL/kg rat body weight.2 For pharmacokinetic analyses, the blood distribution data for each complex (99mTc and iS3Gd data) obtained from each rat were converted to % ID/mL- plasma using the % ID/g-blood data and a plasma volume factor of 58 * 0.58 mL/kg.2

Urine samples were used to determine the amount of each isotope excreted in the urine during the study period.

Study 1 1 .O mmol Gd(DTPA)2-/kg

U2,l) 0.96 (0.31) L(l,2) 0.53 (0.26) U3,l) 0. I8 (0.06) Ul,3) 0.055 (0.026) UO,lY 0.081 (0.014)

0.1 mmol Gd(DTPA)‘-/kg: b U2,l) 0.81 (0.11) W,2) 0.40 (0.21) U3,l) 0.19 (0.11) L(1,3) 0.038 (0.033) UO, 1)” 0.095 (0.013)

0.001 mmol Cd (DTPA)*-/kg U2,l) 0.94 (0.25) L(1,2) 0.65 (0.11) U3,l) 0.28 (0.06) L(l,3) 0.069 (0.013) L(O,lY 0.089 (0.020)

Study 2 L(2,l) 0.98 (0.09) W 92) 0.65 (0.11) U3,l) 0.30 (0.04)

Ul,3) 0.087 (0.013) L(O,lY 0.087 (0.010)

0.63 (0.27) 0.48 (0.29) 0.12 (0.35) 0.059 (0.035) 0.097 (0.018)

0.57 (0.29) 0.46 (0.42) 0.19 (0.66) 0.066 (0.57) 0.111 (0.110)

0.81 (0.42) 0.58 (0.20) 0.22 (0.32) 0.065 (0.44) 0.107 (0.024)

- - -

-

“Calculated using Eq. (5)

Data Analysis

bN = 5; the data from one rat that received 0.1 mmol Gd(DTPA)‘-/kg was found to exceed 2 standard deviations from the mean data for this group. The data for this rat were excluded from the calculation of the average parameters.

Each set of data obtained from the individual rats was analysed separately by CONSAM. lo However, before analyzing the data from individual rats, an analysis via a particular n-compartment pharmacokinetic model was completed using the mean calculated concentration-time plasma and urine data; this was useful for providing initial parameter estimates for model-fitting to the individual data sets.

Average rate constants were calculated from the models developed for each data set (see Table 1). The rate constants obtained by fitting the mean data were within one standard deviation of the average for the individual rate constants. 8

jetted precisely at time 0. Standard, variance-weighted, least-squares techniques were used to fit the models to the data.3 A variance of 2.4% was applied to each rat’s data. This variance was determined empirically’ and accounts for the variability in the data that could be attributed to sampling error.

The plasma and urine data were linked and compared to various open two-, three- and four-compartment (with urinary excretion) pharmacokinetic models. All models incorporated a time delay to account for the transit time through the kidneys/ureters to the urine in the bladder. Initial conditions were not fixed because the dose could not be administered as a bolus; i.e.. 100% of the dose administered could not be in-

Selection of the pharmacokinetic model that best described the plasma distribution and urinary excretion data was made via the F-statistic as presented by Box- enbaum et al.’ F is defined as the ratio of two vari- ances.12 The F-statistic can be used to test whether the decreased variance calculated when the data are fit to a (n + 1)-compartment model is statistically different from the n-compartment variance. WSS were obtained for two-, three- and four-compartment analyses and were used to calculate an F-statistic. The F- statistic is calculated as


F= WSS, - WSS,,+1) x (d.f.1 wss,+ I

(1)

where WSS, is WSS for the n-compartment data,

WSS,,, is WSS for the (n + I)-compartment data, and d.f. (degrees of freedom) is calculated using Eq. (2).

(N - ml+1 d-f* = (N - P), - (N - P),+l .

(2)

When comparing the three- to two-compartment var- iances in the present study, N (= 19) is the number of data points in the distribution and P is the number of adjustable parameters calculated for each pharmacokinetic model (P = 3 or 5 for the two- or three- compartment models, respectively).

F-statistic values indicating a significantly smaller variance, determined via F-tables,3 were used to select the better model. If the F-statistic indicated no significant difference, then the two-compartment model was deemed appropriate.’

Comparisons between the three- and four-compartment models using the F-statistic indicated that the four-compartment model was not significantly better than the three-compartment model for describing our data.

Other statistical evaluations were accomplished via

appropriate t-tests. l2 The variance of each parameter estimate was obtained from the covariance matrix using standard least-squares methods.3

RESULTS AND DISCUSSION

Averaged time-dependent plasma distribution data over the first 60 min for each study are presented in Figs. 1 and 2, respectively. Although all of the data collected were used in the analyses, for illustrative pur- poses only the data points for the first 60 min are shown. Vertical lines through the averaged data points in Figs. 1 and 2 indicate 95% confidence intervals for the Gd(DTPA)‘- data and Tc(DTPA) data, respectively. The confidence interval lines are not presented in Fig. 1 for the Tc(DTPA) data; these data, however, had similar variability. The Tc(DTPA) data points in Study 1 are within the 95% confidence intervals for the Gd(DTPA)‘- data at each dose level.

Statistical analyses, via paired t-tests, between the 99mT~ and lS3Gd blood distribution data in each group in Study 1, at each of the 19 blood sample times, indicated no statistical differences. A similar comparison of the 99mT~ data between Study 2 and each group in Study 1 also indicated no significant differences at the same sampling intervals.

In a previous biodistribution study in rats, Prato et al 21 found a significant difference between the .,

3 E I s 0

8 cl 100 -0 2 8 f

8 5 0 ‘53Gd/Gd(DTPA)2: 0.1 mmollkg

T” 10

0 ‘53Gd/Gd(DTPA)2’: 0.001

11 I I I I I I

0 10 20 30 40 50 60

Time (min)

Fig. 1. Averaged plasma distribution data obtained in Study 1 during the first 60 min post intravenous co-injection of 99mT~(DTPA) and 153Gd(DTPA)2- at 1 .O, 0.1, and 0.001 mmol/kg. The solid lines indicate the program-generated best fit results obtained using a 3-compartment open pharmacokinetic model. Only a single line is apparent because there were no discernible differences between the fitted lines for Tc(DTPA) and Gd(DTPA)‘-. Vertical lines represent the 95% confidence intervals for the Gd(DTPA)‘- data.


? 1 0

I

10 I I I 1 1

20 30 40 50 60

Time (min)

Fig. 2. Mean plasma distribution data obtained in Study 2 during the first 60 min postintravenous administration of 99mTc(DTPA) alone. Vertical lines indicate the 95% confidence interval for each data point. The solid line indicates the program-generated best fit results obtained using a three-compartment open pharmacokinetic model.

blood distributions of 153Gd(DTPA)2- and 99mT~- (DTPA) that had been co-administered intravenously over 5 residence intervals (ranging between 1 and 30 min). In addition, the amounts of ls3Gd and 99mT~ measured in blood, were considerably greater (e.g., 3.8 and 4.2 %/mL-blood for *53Gd and 99mT~ at 1 min, respectively) than was found in the blood of our rats (1.60 and 1.59 %/mL-blood for ls3Gd and WmT~ at 1 min, respectively); these differences increased to 4-fold at 30 min. It is possible that the 50 mg Na pen- tobarbital/kg used to anesthetize the rats in the earlier study21 affected the distribution via decreased cardiac function. ’ Ketamine was used in the present study because it does not decrease cardiac function.

Urinary excretion data are presented in Table 2. Data evaluations using t-tests found no statistical differences between the % ID of each radionuclide measured in the urine at 90 min in the three dosage

Table 2. Urinary excretion of 99mTc(DTPA) and 153Gd(DTPA)2-

Complex Average %

ID (90 min) in urine (SD)

Gd(DTPA)2- (mmol/kg): 0” 0.001 O.lb 1.0

Study 1 ‘s3Gd(DTPA)2- - f32(7) 78 (7) 84 (7) 99mT~ (DTPA) - 78 (10) 73 (2) 80 (4)

Study 2 99mT~ (DTPA) 84 (7)

ONo carrier added. bN=5.

groups in Study 1. A second comparison, made between the % of injected 99mT~ present in the urine at 90 min in Study 1, at each of the dose levels of 1S3Gd-Gd(DTPA)2- co-injected, versus that found at the same time in Study 2, found no statistical differences.

Compartmental Analyses In both studies, the individual sets of data for each

injected complex are best described by the three- compartment open pharmacokinetic model shown in Fig. 3. The time-delay incorporated in the compartmental analysis, compensating for the urine transit

Ureters

t

0

0 Urine

Fig. 3. Schematic of the three-compartment open pharmacokinetic model generated that describes the data presented in Figs. 1 and 2. Differences in the area of the circles for compartments I, 2, and 3 represent the relative differences in V,. The ureters are depicted to indicate the time- delay used in the analysis between the site of elimination and transfer conduit (kidneys and ureters, respectively) and the urine in the bladder.


time from plasma (via the kidneys/ureters) to urine in the bladder, is indicated by the box labeled ureters. Addition of this time-delay resulted in a significant improvement in the fit of the data to the three- compartment model (as well as the two- and four- compartment models) as determined by calculating the F-statistic. The solid lines superimposed on the data points in Figs. 1 and 2 illustrate the model fit to each mean data set. The model generated lines for the 153Gd and ggmT~ data collected in the 3 groups in Study 1 were indistinguishable (Fig. 1).

The three-compartment open pharmacokinetic model indicates that the injected material distributes from the compartmental space defining the site of injection to two separate nonplasma spaces. These spaces have been labeled fast equilibrated space (FES), and slow equilibrated space, (SES) (referring to compartments 2 and 3, respectively). The anatomical locations of these spaces cannot be specified. The plasma distribution data cannot differentiate the model in Fig. 3 from another slightly different three-compartment model that has an interaction between the FES and SES, but no interaction between plasma and SES.’ We elected to present the pharmacokinetic data generated using the model shown in Fig. 3. Multi- tissue pharmacokinetic analyses are in progress to investigate the anatomical locations contained within these compartmental spaces.2g

The sum of apparent volumes of FES and compartment 1 (see below), however, corresponds to that reported for the extravascular space (21@/0),~ and the large apparent volume of SES, which exceeds that of the combined volumes of plasma and FES, suggests a drug-binding phenomenon. Separate plasma protein binding experiments have not, however, confirmed the existence of any drug-binding in plasma, and we are unaware of any studies that have shown drug-binding in plasma for Gd(DTPA)2-.

It was speculated that the SES compartment results from the distribution of unbound lS3Gd or ggmT~. Upon investigating this hypothesis, however, it was concluded that there was insufficient free Gd (~0.2%) and Tc (2-3070) to account for the Gd and Tc concentration in the SES. This conclusion is based on a pharmacokinetic analysis of free Gd (data obtained following intravenous administration of 153Gd(acetate), at 0.001 mmol/kg to rats). In this analysis, the V, and kinetic rates were significantly different from those calculated for the SES with Gd(DTPA)2- or Tc(DTPA).

A single route of elimination was sufficient to fit the data. In this analysis the loss pathway was selected from the plasma space (compartment l), however, it

is not possible from these data to distinguish the proposed model from models with single losses from either of the non-plasma compartments.’

The FES and SES were distinguishable because of the large number of plasma samples collected between 1 and 10 min postinjection. Previous studies that re- solved their data by only a two-compartment model did not have extensive sampling during the first 60 min postinjection. 17,21,24,3L

The possibility that the FES was due to a mixing ar- tifact is unlikely since the first blood sample (60 s post injection) was obtained after approximately five circu- lation times and the maximum rate of disappearance of injectate from the plasma, as determined from the model (see below) was much shorter than the maximum predicted (5.2 min-‘) by the ratio of cardiac output to blood volume. l6

Rate constants (CONSAM L-values) are presented in Table 1 as L(X, Y), where the direction of material transfer is indicated from compartment Y to X; e.g., L(2,l) indicates the rate constant for the movement from compartment 1 to compartment 2. Rate constants were determined by model fitting to each rat’s % ID/mL-plasma data; the average rate constants were then calculated and are reported here.

The rate constant for elimination of each complex from the plasma compartment was determined inde- pendently from the model by calculating the glomerular filtration rate, GFR, from the 90-min plasma data26 for each rat. GFR was calculated by Eq. (3).

GFR = Dose/AUC . (3)

Dose is expressed as counts per min (cpm), and the denominator is the calculated area under the plasma curve (AUC) as determined using Eq. (4).

AUC = (cpm/mL) * time = C (A ;/K;) . (4)

AUC is determined by fitting a double-exponential function (CPlasma = CAie-K”) to the plasma data.28 The respective average GFRs are presented in Table 3. The GFRs calculated are appropriate for rats weighing 375 g (4), and the amount of each radionuclide as- sayed in the urine (Table 2) confirm the respective GFRs calculated.

The rate constant for excretion, L(O,l) was fixed using Eq. (5) and allowed incorporation of the urine data into the model.

L(O,l) = GFR/& (5)


Table 3. Calculated average GFRs

Complex GFR (mL/min): (SD)

Study 1 1 .O mmol Gd (DTPA)2-/kg

Gd (DTPA)2- Tc (DTPA)

0.1 mmol Gd (DTPA)‘-/kg” Gd (DTPA)‘- Tc (DTPA)

0.001 mmol Gd (DTPA)‘-/kg Gd (DTPA)‘- Tc (DTPA)

Study 2 Tc (DTPA)

2.82 (0.73) 2.81 (0.65)

2.96 (0.62) 2.91 (0.56)

2.86 (0.53) 2.90 (0.49)

2.97 (0.73)

aN=5.

V,, , the apparent initial volume of distribution in the plasma compartment, i.e., the site of injection, was calculated using Eq. (6) (see Table 4).

V,, = V,, (mL/kg) = Dose/A . (6)

In Eq. (6), Dose is expressed as cpm and “A” is they- intercept, expressed as cpm/mL plasma, for a single exponential fit to the l-4 min data (Figs. 1, 2). The apparent volumes of distribution (V,) were also calculated for the FES and SES, I/dtn), using Eq. (7)20

VdmL) = v,l * L(n, 1)

L(l,n)

Table 4. Average V, for each compartment

Mean V, (mL): (SD) Compartment No.

Complex 1

Study 1 1 .O mmol Gd (DTPA)‘-/kg

Gd (DTPA)2- 32 (12) Tc (DTPA) 34 (6)

0.1 mmol Gd (DTPA)‘-/kgU Gd (DTPA)2- 29 (4) Tc (DTPA) 31 (6)

0.001 mmol Gd (DTPA)‘-/kg Gd (DTPA)2- 31 (18) Tc (DTPA) 30 (9)

Study 2 Tc (DTPA) 36 (5)

2 (FES)

47 (44) 69 (31) 59 (32) 109 (48)

36 (49) 50 (47)

82 (15) 122 (83)

43 (67) 41 (42)

57 (17)

3 @ES)

104 (54) 115 (67)

127 (36)

aN=5.

where L(n,l) is the rate constant for exchange from the plasma to compartment n and L ( 1, n) is the rate constant for exchange in the opposite direction. The average I$‘s are presented in Table 4.

The apparent I/d’s for compartment 1 in all groups were approximately 340% of the calculated total plasma volume (9.1 f 0.8 mL) based on the reported factor of 24.4 mL-plasma/kg.2 (Independent mea- surements of 99mTc-labeled erythrocytes’* yielded a similar result of 24.6 f 1.7 mL/kg.) This considerably larger-than-plasma V, for compartment 1 was also found in clinical investigations.32 Clearly, the initial rapid dilution of injected material reflects a very high rate of distribution of material from the injection compartment following intravenous administration.

Although the anatomical locations for the FES and SES cannot be specified, the preliminary results of pharmacokinetic analyses of individual organs29 seem to indicate that kinetic rates similar to those generated for the FES correspond to rates obtained for the interstitial space of organs such as heart, lungs, skeletal muscle and skin, whereas the kinetic rates obtained for other tissues, e.g., liver and small intestines, seem to agree with rates found for the SES.

Simulations of the three-compartment model, using the average rate constants, were used to investigate the time course of Gd(DTPA)2- in the nonplasma spaces.’ Gd concentration has relevance to changes in signal intensity in MRI.‘5*27 It is thought that the tissue concentration should be at least 0.05-O. 1 pmol Gd/mL in order to produce obvious image enhancement.22 The time-dependent drug concentration curves for Gd(DTPA)‘- in each compartment for the group injected at 0.1 mmol Gd(DTPA)2-/kg in Study 1 were calculated using Eq. (8)

= (Vo ID,,) /lOO) * D(pmol)

Total I/dtnl (mL) (8)

where % ID,,, is the fraction of the total injected dose determined in compartment [n] at time [t 1, D is the total amount of Gd(DTPA)2- administered expressed in pmol, and Total l$tnl, expressed in mL, is V, for compartment [n] .

The time-dependent Gd(DTPA)‘- concentration curves are presented in Fig. 4. These data suggest that MR image enhancement in rats would be greatest for the FES (with peak enhancement) at about 2 min post injection of Gd(DTPA)‘-; greatest enhancement for the SES would not occur until about 10 min postinjection. The greatest difference between FES and SES is


- Compartment 1 (Plasma)

- Compartment 2 (FES)

h - - Compartment 3 (SES)

0 10 20 30 40 50 60

Time (min)

Fig. 4. Average calculated time-dependent concentration of Gd(DTPA)2- (umol/mL) in each compartment at a dose of 0.1 mmol/kg in Study 1. Concentration is based on the calculated Vd’s and calculated distributions in each compartment. To am- plify FES and SES, the plasma data are divided by 0.58 for graphical presentation.

obtained at about 2 min. Eventually, when appropriate multitissue distribution data have been collected, it should be possible to simulate and predict optimal MR affects in a specific tissue.29

In clinical situations, it generally takes several min to acquire a normal 7’r-weighted spin echo image; however, image acquisition time can be significantly shortened (cl min), for example, by using a Gd- chelate in conjunction with faster imaging sequences (such as gradient echo). l4 Our studies indicate that optimal MR signal enhancement occurs within a few min following intravenous administration of Gd(DTPA)2- and agree with numerous clinical investigations. One significant conclusion from the present study is that future pharmacokinetic evaluations will require deter- mining the distribution and elimination kinetics of target-tissues/organs rather than only the blood. By using the calculated rates, it may then be possible to determine the optimal time post injection of a Gd- chelate to obtain the greatest signal enhancement and contrast effect.

In summary, time-dependent plasma distribution data obtained following intravenous injection of radiolabeled Tc(DTPA) and Gd(DTPA)2- are best fit by a three-compartment open pharmacokinetic model. Two nonplasma compartments could be distinguished from the data, one with a rapid and the other with a slow plasma equilibrating time. A single excretion pathway from plasma to urine was sufficient to describe the data. The rate of excretion was similar to the rate predicted for glomerular fihration. There were no dose dependent differences in the plasma distribution kinetics or urinary excretion kinetics for IV administered Gd(DTPA)2- for the doses tested. Simulation

of the Gd(DTPA)2- compartmental distribution based on the pharmacokinetic model indicated that the greatest Gd(DTPA)2- concentration occurs in the nonplasma fast equilibrating compartment between 2 and 20 min postadministration in the rat.

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4.

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