which is released during the decay of 1231.The resultingseptum penetration, when employing a high-resolutionlow-energy collimator, is sufficient to reduce the image

quality even if extremely pure 1231is used. Consideringall factors, a substance would be preferable which canbe labeled with technetium-99m (@mTc)and is excretedby tubular secretion to a sufficient extent.

In this context, a series of diamide-dithiol-(N252)ligands was developed on the basis of the work byDavison et al. (1,2), revealing pharmacokinetic properties similar to OIH (3—10).The first clinical studieshad shown the triamide-monothiol-(N3S) complex Tc99m-mercaptoacetylglycylglycylglycine (@mTc@MAG3)to be the most appropriate substance to replace OIH(11,12). Preliminary pharmacokinetic studies both in

animals and in humans showed notable differencesbetween this new radiopharmaceutical and OIH withrespect to the clearance, biological distribution andplasma protein binding (6,11,13—17).

The aim of this paper is to present a systematicinvestigation of differences existing between 99mTc..MAG3 and OIH in humans on the basis of variousparameters. The results will be interpreted with respectto the reason for the lower clearance of99mTc@MAG3ascompared to hippuric acid derivatives, the affinity of

the 99mTccomplex to the tubular transport system, itspresumed hepatobiliary excretion, and its renal elimination mechanism, in order to allow better comprehension of the quantitative results obtained from renalfunction studies using @mTc-MAG3.

MATERIALSAND METHODS

All patients, either with native or with transplant (Tx)kidneys, were referred for evaluation ofthe renal function andgave their written consent. This study was approved by theEthical Commission of the University of Heidelberg and theFederal Board of Public Health (Bundesgesundheitsamt).

RadiopharmaceuticausThe precursor S-benzoyl-mercaptoacetyl-glycylglycylgly

cine was synthesized as previously described in another paper(14). All intermediates were characterized by NMR-, i.r.- andmass spectroscopy. The final product was additionally identified by elemental analysis.

Technetium-99m-mercaptoacetylglycylglycylglycine(@‘Tc-MAG3)is introduced to replace o-iodohippurate(OIH)for renal function studies. For interpretation of clinicalfindings, extensive pharmacokineticstudies were performedon patients.Theseshowedthat @“Tc-MAG3,cornpared with OlH, has a higher plasma-protein binding, anessentiallyhigher intravascularconcentration,a smallervolume of distribution and, with practically identical biologichalf-lives, a correspondingly lower clearance. Simultaneous steady-statemeasurementsresulted in a 1.5-foldhigher clearance of OlH than of @“Tc-MAG3(n = 124).Competitiveinhibitionof the tubulartransportsystembyp-arninohippurate (PAH) (20 patients) revealed a distinctlyhighersuppressionof the @“Tc-MAG3clearancethan ofOIH which indicates a lower affinity of the @“Tccomplexto the tubularcell. The plasmaextractionefficienciesofboth agents, measuredduring surgery (n = 5), did notindicate an extrarenal elimination of @Tc-MAG3.This newradiopharmaceutical is a pragmatic alternative to OlH andoffers advantages not only for scintigraphic imaging but is

also suited for quantitative renal function studies.

J NucIMed 1990;31:1285—1293

though o-iodohippuric acid (OIH) essentially fulfills the pharmacokinetical requirements for a renalfunction agent, the necessity ofradioactive iodine labeling leads to distinct disadvantages for routine use: iodine-l 3 1 (‘@‘I)labeled OIH has a poor imaging qualitycaused by the high energy of 364 keV and leads to ahigh radiation exposure particularly due to the betacomponent of the radioactive decay. The other frequently used label, 1231,seems to solve these problemsat first, but since it can only be produced in a cyclotronand has a half-life of 13 hr, logistic problems arise inthe distribution of this very expensive iodine isotopeand the radiopharmaceutical, respectively. Another disadvantage consists in a high photon energy of 530 keY

ReceivedSept.12,1989;revisionacceptedFeb.13,1990.Forreprintscontact:BemdBubeck,MD,BSc,Dept.of NudestMedi

dna, Wiversity of Heidelberg, Im NeuenheimerFeld 400, D-6900 Heideiberg.WestGermany.

1285Pharmacokinetics of Technetium-99rn-MAG3 in Humans •Bubeck et al

Pharmacokinetics of Technetium-9 9m-MAG3in Humans

Bernd Bubeck, Wolfgang Brandau, Ernst Weber, Tilman Kälble,Niranjan Parekh, and Peter Georgi

Department ofNuclear Medicine, University ofHeidelberg, Department ofNuclear Medicine, University of Münster,Departments of Urology and Physiology, University ofHeidelberg; and Department ofBiosiatistics, German CancerResearch Center, Heidelberg, West Germany

Technetium-99m-pertechnetate was obtained from a commercial generator system. Labeling was performed, with thekit procedure described elsewhere (6), in —95%radiochemicalyield and 99mTCMAG was purified by high-pressure liquidchromatography (HPLC) prior to application (14). The finalsolution contains 9QmTCMAGwith a specific activity of>7.4GBq/mg (200 mCi/mg).

Iodine-l 3 l-OIH was prepared according to the methodpublished by Sinn et al. (18) with a specific activity of -‘-37MBq/mg ( I mCi/mg). The radiochemical purity of bothagents was >99%.

Bindingto Red BloodCells and PlasmaProteinsWithin 10 mm following the withdrawal, the whole blood

was centrifuged using a swing-out rotor at 700 g for 20 mm.The count rates of each 1 ml whole blood and 1 ml plasmawere measured in a well-type counter. Physical decay correction and, for simultaneous measurements, a correction forcross-talkof 1311into the 99mTcchannel (16.5%) were performed. For the calculation of the binding to the red bloodcells (RBCs), the hematocrit (HC) value was determined witha Sysmax system CC 780 (Digitana, Hamburg, West Germany). In this instrument, the whole blood is diluted to adefined volume; the number and size of RBCs are recordedby electric resistance detection passing a transducer aperture.Plasma trapping between RBCs cannot influence the result.

For the determination of the plasma protein binding, theplasma was ultrafiltered in an Amicon cell through a Diaflowmembrane PM 30 (exclusion limit 30,000 Dalton; 5 bar N2-pressure). For the calculation of the protein bound fraction,the protein content of the plasma was assumed to be 7.2 g/100 ml.

p-Aminohippuric acid (PAH) was measured according tothe procedure developed by Bratton and Marshall (19) andmodified by Deetjen and Sonnenberg (20).

Compartment AnalysisAccording to Sapirstein et al. (21), the time-activity curves

ofthe blood and the plasma, respectively, can be described bytwo components to be calculated by the following equation:

y = Ae@' + Be@'.

From the counted activity concentrations y at time t, thecompartment coefficients b1 (fast component) and b2 (slowcomponent)and the biologic half-lives T―andT0, respectively,as well as the distribution volumes V1 and V2, and the slopeclearances can be calculated (21,22). In order to determinethese parameters, 14 patients received 7.4 MBq [‘31IJOIHand7.4 MBq 99mTcMAG simultaneously. Blood (3 ml) wasdrawn 2, 5, 10, 17, 25 and 30 mm postinjection.

Steady-State ClearanceForty minutes after i.v. application of 11.1 MBq [‘311]OIH

and 18.5 MBq 99mTc..MAG3simultaneous clearance determinations under steady-state conditions were performed in124 patients (48 patients with transplant (Tx) kidneys) by aspecial feedback-controlled infusion pump device (23). Thecalculation was based on the activity dose required for maintenance of the steady state (not the activity eliminated withthe urine!) and the plasma concentration in this condition.

The patients' serum creatininevaluesrangedbetween0.3 and5.3 mg/lOO ml (mean = 1.5) on the day they were examined.

PAHLoadingTwenty patients with native kidneys received an infusion

of 80 mg PAH/kg body weight (50 ml volume) within 5 mm,immediately after basic clearance measurement in steadystate. Maximum plasma concentrations of 30—40mg PAH/100 ml were reached. Serum creatinine amounted to valuesbetween 0.7 and 2.2 mg/bOOml (mean = 1.1).Three differenttime intervals were selected for the clearance calculation:second to fifth minute during the PAH infusion, first to tenthminute after the infusion and eleventh to twentieth minutefollowing PAH application.

LipophilicityIn order to determine the octanol-water partition as a

measure for the lipophilicity ofthe two radiopharmaceuticals,ig of 0. 1 N citrate buffer (for pH = 4.0) and lg of 0. 1 Nphosphate buffer (for pH = 6, 6.5, 7.0, 7.4, respectively) weremixed togetherwith ig octan-l-ol. After adding lOMl99mTcMAG3and [‘3IJOIH(—‘4MBq each), the sampleswere vortexed for 3 mm, centrifugedat 2,500gfor 10 mm and thenseparated. Two-hundred mg of the water and the octanolphase, respectively, were measured in a well-type counter. Thecalculation (see Table 3) was performed according to thefollowing equation:

Lipophilicity [%] = cpm(octanol) x 100 / [cpm(octanol) +

cpm(H20)J.

RenalArterio-VenousDifference(ExtractionEfficiency)

In thesepatients(n = 5)a unilateralnephrectomydue to amalignant renal tumor was to be performed. Steady-stateclearances of @mTc-MAG3and [‘31IIOIHwere determinedduring the week prior to surgery. [3'IJOIH (4 MBq) and99mTCMAG (1 1 MBq) were administered intraoperativelyafter uncovering the diseased kidney. Five to 10 mm afterwards, blood samples were taken from the renal artery andrenal vene simultaneously, and the activity concentrationswere then measured according to the method described above.The serum creatinine value examined during the operationranged between 0.6 and 1.2 mg/lOO ml. The intraoperativesystolic blood pressure differed from preoperative clearancemeasurements by 15% at most.

Statistical ModelsFor examinationof differences,the Wilcoxontest for pair

differences was used, as well as the U-test to compare twoindependent random samples. The significance was definedto be p@ 0.05 and all regressionanalyseswere made for p@0.05 (95%-confidence intervals).

RESULTS

The binding of OIH to red blood cells amounted to15.3% ±4.1 s.d. (n = 32; HC(mean) = 37.3%) and of99mTcMAG to 5. 1% ±3.3 s.d. (n = 49; HC(mean) =38.2%).

The plasma protein bindings of PAH, OIH, and99mTcMAG revealed highly significant differences

1286 TheJournalof NuclearMedicine•Vol.31 •No.8 •August1990

p-amino-hippurateo-iodo-hippurateTc-MAG3Maherand

Tauxe(24)18.3 ±6.1(n=6)66.8

±1.9(n=5)—Tayloretal.(11)—66.2±6.987.5±2.6(n=8)(n=8)Taylor

et al. (25)—53.1 ±8.7(n=12)78.6

±7.9(n=12)Our

results26.1 ±6.7(n= 20)70.7

±5.0(n = 32)90.1

±2.8(n = 50)

Plasma(n = 14)Whole blood (n =10)o-l-hippurateTc-MAG3o-I-hippurateTc-MAG3CI*[mI/mm]41

2 ±169265 ±98639 ±348449 ±228b1[min'J0.345±0.1650.353 ±0.1660.460 ±0.3000.476 ±0.356b2[min1]0.033±0.0120.033 ±0.0120.033 ±0.0100.032 ±0.013TA[mini2.50±1.282.37 ±1.032.21 ±1.342.31 ±1.62T8[mm]26.0±18.625.0 ±13.522.6 ±6.624.7 ±9.5v1*[I]5.34±1.833.67 ±1.087.66 ±4.405.55 ±2.99v2*[I]5.54±2.763.38 ±1.227.77 ±1.726.01 ±1.22vi-

+ v2-[I]10.88 ±3.757.05 ±1.5815.43 ±4.6211.56 ±3.12vi+ V2[% BW]16.6 ±5.610.8 ±2.323.1 ±7.017.3 ±4.9*

Related to 1 .732 @ysurface

TABLE IPlasma Protein Binding (% ±s.d.)

(p@ 0.0 1). For PAH, it averaged 26. 1%, for OIH 70.7%and for 99mTCMAG 90. 1% (Table 1). Since only thenon-protein bound fraction of a substance can be filtered glomerularly (6,24), not more than about 2% of99mTc-MAG3are ultrafiltered, assuming a normal filtration fraction (FF) of the human kidney of 20%. Thus,the clearance of 99mTc-MAG3 corresponds approximately to the “tubularextraction rate―(TER) of thissubstance. [Definition: The TER corresponds to thevirtual plasma volume per minute from which a substance (related to its plasma concentration in the renalartery) is completely removed by tubular extraction].Therefore, the clearance of 99mTc..MAG3 shall be designated as TER(MAG3) in the following.

In 10 of 14 patients, the compartment analysis (21)was not only performed on the basis ofplasma, but alsoofwhole blood samples (Table 2). No significant differences of the biologic half-lives TA and TB and thecompartment coefficients b1 and b2, respectively, between 99mTCMAG and OIH (p > 0. 1) were revealed.

The differences between the two radiopharmaceuticals with respect to V1 and V2, based on the plasmavalues, were highly significant (p@ 0.01). The totalvolume of distribution (V1 + V2) of OIH and 99mTc@MAO3 amounted to 16.6% and 10.8% of the bodyweight (BW), respectively. The clearance (Cl) ratio99mTcMAG/OIH amounted to 0.66 (±0.11 s.d.) in

the plasma and 0.74 (±0.13 s.d.) in the whole blood(Table 2).

After compartment distribution in vivo, the ratio ofthe plasma concentrations 99mTc-MAG3/OIH (relatedto the injected dose) revealed no significant dependenceon the time of withdrawal (intra-individual standarddeviation between the tenth and the thirtieth mm postinjection of max. 5%) and ranged from 1.06 to 2.12(mean = 1.57). Figure 1 presents the mean (relative)time-activity concentrations and half-life exponentialsin plasma (semilogarithmic) of all 14 patients duringthe first 30 mm postinjection, thus clearly pointing outthe difference between the two radiopharmaceuticals inthis regard. The respective ratio in whole blood was1.36 (1.01 —1.76).

In simultaneous clearance measurements understeady-state conditions (n = 124), the OIH clearanceranged between 35 and 654 ml/min (mean = 299),whereas the TER(MAG3) lay between 4 and 441 ml!mm (mean = 203). Figure 2 shows the correlation ofthese values with the corresponding confidence intervals (r = 0.94; p :@0.05); the ratio of TER(MAG3)/OIHclearance averaged 0.67.

PAH loading was performed in 20 patients followingthe basic clearance measurement, revealing a significantdecrease in the 99mTc-MAG3 clearance already in thecourse ofthe infusion ofPAH. Within the first 10-mm

TABLE2Compartment Analysis (mean ±s.d.)

1287Pharmacokinetics of Technetium-99m-MAG3 in Humans •Bubeck et al

pH4.0pH 6.0pH 6.5pH 7.0pH7.4OlH82.393.982.601

.691.61Tc-MAG36.050.200.100.080.07

_____- 99mTC_@GS.

Co0

S.

CwU -1C0

S.,

E

: -20

FIGURE1Relativetime-activityconcentrationsandhalf-lifeexponentials(two-compartment-model) of @‘Tc-MAG3and [131l]OlH inplasma(meanof 14 patients,semilogarithmicgraph).

interval post-PAH, the clearance of OIH was 69% andthat of 99mTCMAG 2 1%, as compared to the basicvalues. During the second period (eleventh to twentiethminute post-PAH), the clearance of OIH and 99mTc@MAG3increased to 82% and 36%, respectively, due tothe continuous reduction of the competitive inhibition by PAH (Fig. 3); all these changes were significant(p@ 0.05).

The octanol-water partition only reached a high lipophilicity for OIH at pH 4.0 (-“-82%).The remainingOIH values and all 99mTc@MAG3values at pH 4.0—7.4were clearly below 10% (Table 3).

Table 4 demonstrates the extraction ratios 99mTc@MAG3/OIH in the patients during the operation, determined by measurement of the renal arterio-venousdifference (extraction efficiency) as well as in the preoperative phase, calculated with the aid of clearance

values in steady state. The ratios of the extractionefficiencies lay between 0.56 and 0.78, and the clearance

E5,)

C

EE

04

U,I-

FIGURE2Correlationof the simultaneouslydeterminedTER(MAG3)withthe OIHclearanceundersteady-stateconditions.

—.—.—.— = [131@ OIH

-@- -‘- -v

beforePAH duringPAH 1—10mm. 11—20mm.afterPAH after PAH

—3U 10 . . . 20

Time p.i. (nnn)30

FIGURE3ChangesintheOIHand @‘Tc-MAG3clearances,respectively,duringvarious intervalsunder PAHloading(n = 20).

ratios between 0.66 and 0.74. The differences observedin the individual patients were not significant (p > 0.1).

DISCUSSION

In agreement with the results obtained by other investigators(24,25), the plasma protein binding of@mTc@MAG3 amounting to 90%, was distinctly higher thanthat of OIH, which reached 7 1% (Table 1). The discrepancy appearing in values found by Taylor et al. in1986(11)and 1987(25)wasnotexplainedby theauthors. Taylor and Eshima (13) reported of a reduction ofthe protein binding ofOIH (by 68%) and 99mTc@MAG3 (by 49%) in rats under mannitol diuresis, ascompared to (other) control animals in normal diuresis.Our own in vitro studies showed no change of theprotein bound fraction of 99mTc..MAG3 after a 1:10(n = 4) or 1:100 (n = 3) dilution with 0.9% sodiumchloride (unpublished results).

The higher protein binding of @mTc-MAG3in comparison to OIH may be the main reason for the higherintravascular concentration of@mTc@MAG3, which correlates with the distinctly lower volume of distributionof@mTc@MAG3than ofOIH (Table 2). The volume-ofdistribution ratios 99mTc@MAG3/OIH coincided withother investigators (25,26-28). The contradicting results obtained by Taylor et al. (11) are now explainedby the authors (28) and are no longer opposed to ourresults.

In agreement with Taylor et al. (11), the compartment coefficients (b1 and b2) and the half-lives in both

TABLE3Lipophilicity[%]

(Octanol/WaterPartition)

steadystate y —a 4 bxa -0.54

(•Safly/x 0.67) b =0.68

(•—Tx-patient)

n =124p 0.05r =0.94

asp 59

o-Iodo-hippurateQearance(ml/minhl.73m')

1288 The Journal of Nuclear Medicine •Vol. 31 •No. 8 •August1990

Pre-operative:steady-stateclearanceDuring

operation:extractionefficiencyTc-MAG@Tc-MAG3PatientOIHOlHOP

10.720.560P30.660.760P40.720.760P50.740.580P60.720.78mean

±s.d.0.71 ±0.030.69 ±0.11

0 20 40 60 80 100

TABLE4ExtractionRatios

C.)LUI-

C0U

000C0

U‘5

KLU

‘5

5-

Tc-MAG,

PlasmaProteinBinding (PB) (%)

FIGURE4The TEC as a hypotheticalfunction of the degree of plasmaprotein binding (y = 1 .0 —0.0031 eoo@).

represent a compromise between accuracy and practicability (32—34).To determine accurate and reproducible clearance values, a steady state is required. Wecarried out steady-state-clearance measurements simultaneously with 99mTcMAG and [‘311J01H(n = 124;Fig. 2), which resulted in an average clearance ratio99mTCMAG/OIH of 0.67 with a high correlation coefficient (r = 0.94), thus confirming the theoreticalexpectations (see above). In contrast to Jafri et al. (35),who calculated the same slope “b―in addition to acomponent “a―of 40 mi/mm for the linear regressionequation “y= a + bx―,we found a negligible value of0.6 ml/min for “a.―The reasons for this difference aremost probably that they only examined very few cases(n = 12) and used the slope technique.

The “tubularextraction rate―of an agent, which isrenally secreted but not reabsorbed, can be calculatedon the basis of its clearance and its protein-boundfraction; for 99mTCMAG it nearly corresponds to itsclearance due to its very high protein binding in humans, designated as TER(MAG3) (see Results). Knowing that the clearance of PAH is higher than the clearance of OIH by a factor of 1.2 (mean value from 7references in (36)) and that the OIH clearance, asshown, is higher than the 99mTc..MAG3clearance by thefactor 1.5, a “tubularextraction coefficient―(TEC) canbe calculated for these agents, which indicates the portion of the substance extracted from the peritubularcapillary blood and plasma, respectively. This parameter is required to compare the extent oftubular secretionof agents with different glomerular filtration fractions.Since PAH is extracted completely in the cortical nephrons from the plasma by the tubular transport system,its TEC amounts to 1.0. The TECs for OIH and @mTc@MAG3were calculated to be 0.83 and 0.55, respectively(37).

As demonstrated in Figure 4, there could be a connection between plasma protein binding and TEC due

compartments, respectively, reveal no significant differences with respect to the two radiopharmaceuticals(Table 2). This means that the elimination half-lives arenearly identical for both substances and also correspondto urine measurements (11), in which -‘-70%of theadministered dose of both radiopharmaceuticals havebeen excreted within 30 mm postinjection.

With identical elimination half-lives for @mTc@MAG3and OIH, and a plasma concentration of @mTc=MAG3that is constantly higher by a factor of 1.57 (Fig. 1), theplasma clearance (in slope) for OIH is theoreticallyexpected to be higherthan that for @mTc@MAG3by thisfactor and was calculated to be 1.52 (Table 2). Inagreement with other authors (11,29) the averagewhole-blood-clearance ratio @mTc@MAG3/OIHreaching 0.74 was found to be notably higher (p@ 0.05) thanthe respective plasma-clearance ratio (0.66). This isexplained by the higher binding of OIH to RBCs ascompared to 99mTc..MAG3(15% versus 5%), since thefraction ofthe substance bound to RBCs is not availableto the tubular cell for extraction (30). This means that,in contrast to the supposition of Taylor and Eshima(13), the plasma clearance and not the whole bloodclearance is clinically relevant.

We agreewith Kim et at. (31) that the clearance of asubstance does not depend upon the volume of distribution, which, in turn, is mainly determined by thedegree of protein binding, but on the renal extractionefficiency, which may also be influenced by the plasmaprotein binding (Fig. 4). The supposition by Jafri et al.(26) that the smaller volume of distribution of @mTc@

MAG3is the resultofa smaller fraction bound to RBCsand of a weaker protein binding, does not apply and ismerely hypothetical, respectively, because this difference also exists when the calculation is based on plasmavalues and there were, until now, no data relating tothe strength of the protein binding. Furthermore, themolecular sizes of both radiopharmaceuticals do notessentially differ from each other, following that this isan unlikely explanation for a slower diffusion of@mTc@MAG3 from the plasma than of OIH.

Clearance measurements in slope are generally disputed, especially in pathologic conditions, and only

Pharmacokinetics of Technetium-99m-MAG3 in Humans e Bubeck et al 1289

larly filtered fraction of OIH is of negligible influence).These observations coincide with animal experiments(13) and lead to the conclusion that 99mTCMAG has a

clearly lower affinity to the tubular transport proteinsthan OIH.

Further investigations have to demonstrate whethera drug treatment might influence the TER(MAG3) inthis respect. However, simultaneous examinations oftransplant patients have shown that the uptake of@mTc@

MAG3in the renal parenchyma is similar to OIH evenin cases of severely impaired renal function and thisleads to diagnostically useful renograms (12,42).

Blaufox (43) discussed the “non-ionicdiffusion―(tubular reabsorption oflipophilic molecules) as a possiblereason for the difference between the clearances of PAHand OIH. Theoretically, this might also represent onecause for the lower clearance of 99mTc-MAG3 against

OIH. The determination of lipophilicity by means ofthe octanol-water partition revealed far less pH-dependent changes for 99mTcMAG than for OIH in the rangebetween pH 7.4 (normal blood pH) and pH 4.0 (extremely low urine pH) (Table 3). In agreement withelectrophoretic measurements (44), demonstrating that99mTcMAG is negatively charged even at pH 4.0, anon-ionic diffusion of 99mTc@MAG3can be excluded.Additionally, a tubular retransport of99mTc@MAG3during water reabsorption, a “solventdrag,―cannot beresponsible for the clearance differences because theTER(MAG3)would then have to increase under accelerated diuresis; this was observed neither under furosemide nor under hydrochlorothiazide diuresis (37).

The intraoperative measurements revealed that theratios of the plasma-clearance values determined preoperatively do not differ significantly from the ratios ofthe extraction efficiencies (EEs) measured during surgery (Table 4). In case of an additional hepatobiliaryexcretion of 99mTc..MAG3,as reported by several authors using kit preparations (26,28), these ratios would

a - 0 62 consequently have to differ from each other if our

b = 0.0002 clearance technique is used (see Materials and Meth

ods).Taylor and Eshima (13), who found a lower clearance

of99mTc@MAG3than ofOIH in rats, calculated a higherextraction efficiency of@mTc@MAG3in relation to OIH“inspite of―the higher protein binding of@mTc@MAG3.The discrepancy of the EE to the clearance values aswell as the higher protein binding are not really contradictory, because the authors based the EE calculationon whole blood and not on plasma. Since the fractionof OIH bound to RBCs is higher than that of 99mTcMAG3, the EE is mathematically shifted in favor of99mTcMAG However, this is not admissible, since theRBC-bound fractions of both agents do not participatein the process oftubular secretion because the diffusionof the radiopharmaceuticals out of the RBCs into theplasma is very slow (30). A respective correction (45)

y@ a + bx

.@ o@# -a S 0 A& _____

(•@ Tx- patient)

to the fact that in substances which are bound to plasmaproteins to a high degree, like OIH and 99mTc..MAG3

the peritubular transit time is too short for completedissociation of the respective agent from the plasmaprotein, so as to be available for tubular secretionfollowing subsequent diffusion into the extracellularfluid. This would also explain the observation made by

Harth et al. (38), stating that an increase in renalperfusion leads to a decrease in PAH extraction, whichthey supposed was caused by the altered form andvelocity of the blood flow. The reports of other authors

(I1,13,39,40)whichpointoutthattheclearancedifferences between OIH and 99mTCMAG are distinctlysmaller in rats than in humans, also stated that theprotein binding of both agents in rats is essentiallylower. This supports the theory that the level of TECdepends on the protein binding (Fig. 4).

According to this hypothesis, the extent of proteinbinding of PAH within ±1 s.d. (vertically shaded area

in Fig. 4) would only have minimal influence on the

TEC of PAH, whereasOIH would already reach valuesranging between 0.79 and 0.88 in this area. The proteinbinding of@mTc@MAG3 in the range between 87% and93% (i.e., ±1 s.d.) even leads to variations of TEC ofbetween 0.45 and 0.6. These deviations ofthe respectiveradiopharmaceutical from the mean TEC value mightbe the cause for the infrequently observed but distinctdeviation of the ratios TER(MAG3)/OIH clearance(Fig. 5), which is nearly independent of the renal func

tion. It will have to be examined in the future to what

extent a drug therapy might influence the plasma protein binding of 99mTCMAG and consequently theTER(MAG3) in these patients.

The PAH loading, which was introduced by LumWinkel (41 ), has shown that the clearance of 99mTcMAO3 can be influenced to a higher degree than theclearance of OIH (Fig. 3; the slightly higher glomeru

n —124

1.5- p'O.O5r - 0.18

asUC‘5S.‘5as

S.,

‘:@1''.@@T: :@

@-@oi@@@ 4@@@

o—Iodo—hippurateClearance (ml/min/l.73 m')

FIGURE5The ratio [TER(MAG3)/OIHclearance] shows only a slightdependenceof the renal function(= OlH clearance),butdistinctinterindividualdeviations.

1290 TheJournalof NuclearMedicine•Vol.31 •No.8 •August1990

is not necessary and would falsify the results. Thereported extraction efficiencies for 99mTc-MAG3 (13,45) do not correspond, as assumed (13), and cannot be

compared because one value was determined fromplasma (45) and the other from whole blood (13).

CONCLUSION

Technetium-99m-MAG3 demonstrates renal uptakeand elimination characteristics which are analogous toOIH, even in cases of severely impaired renal function(12,25,26,28,42).Therefore,it can replaceradioiodinated OIH in qualitative renal function diagnostics withall the advantages originating from the Tc-99m label(Fig. 6), including the additional evaluation ofthe renalperfusion during the first pass.

Technetium-99m-MAG3 has a distinctly lower affinity to the transport proteins of the tubular cell than

OIH and possibly a higherrangeofdeviation regardingthe extent of the tubular extraction due to the highplasma protein binding. It would have to be studied inspecial patient groups, whether these pharmacokinetic

differences are useful concerning differential diagnosticsor whether they impair the accuracy of quantitativemeasurements. A strict correlation between theTER(MAG3) and the OIH clearance exists in the majority of cases, so that quantitative clearance measurements in clinical routine appear to bejustified. A simpleslope-clearance method, developed by Tauxe et al. forOIH (46,47), was modified and validated for 99mTc@MAG3 with the aid of steady-state-clearancemeasurements (37,48). Similarly, Russell et al. (49) modifiedthe Tauxe algorithms using an 8-point-slope-clearancecalculation.

26. 06.81

0—1mm 1-2 mm

The I .4-fold higher intravascular concentration of99mTcMAG than ofOIH may result in a slightly higherradiation exposure ofthe kidneys by 99mTc@MAG3thanby [‘231]OIH(50), although the elimination half-lives ofboth radiopharmaceuticals are nearly identical. In casesof impaired renal function, however, the shorter physical half-life of @mTcversus 1231can lead to a lowerspecific radiation dose using 99mTc@MAG3.

The fact that neither hepatobiliary excretion (16) normetabolization(51) ofHPLC-purified 99mTc@MAG3hasbeen observed in patients, confirms the presumptionthat the accumulation in the liver and the scintigraphicvisualization of the gallbladder are due to by-productsformed during the complex synthesis (14). For thisreason and with regard to the accuracy of quantitativeclearance measurements, the requirement for commercially available kit preparations, that 99mTc..MAG3 willbe delivered in reproducible radiochemical yields of

95%, must be fulfilled.

ADDENDUM

MUller-Suur and Müller-Suur(52) have most recently reported about excretion characteristics of 99mTc@MAG3in rats.In the context of the hypothetical dependence of the 99mTc@MAG3clearanceon the highprotein binding,they stated that“othersubstances predominantly protein bound have notshown an increased clearance when their protein binding isreduced,―which, according to them, was reported by Ochwadtand Pitts (53). In contrast to this statement, these authors(53),investigatingtubularlysecretedagentsindogs,observedthat “increasingthe percentage of free phenol red by loweringplasma proteins leads to a specific increase in phenol redsecretion.― Furthermore they assumed that “otherfactors,perhaps connected with the different accumulation of such

FIGURE6Left kidney:Relativereducedtubulosecretory function and outflow obstruction with accumulation of @“Tc-MAG3in thepelvicalycealsystem(favourabledemarcationwith half-intensityimaging) in a young patient with left-sidedmegaureter (excellent visualizationpost-void in supine position). Right kidney:Normaltubularfunctionwith slightactivity retention in the renal pelviswithout pathological significance. Theclearanceindex as shown, representstheaveragerenaluptake(cps)betweenthe 60thand 100―sec postinjectionofbothkidneys(usedfor splitclearancedetermination) related to the injecteddose,attenuationcorrected(54),andadjustedfor 1.73m2bodysurface.Thisisof specialsignificancefor theintraindividualfollow-up (e.g., pre- and postoperative)of infantsandyoungchildrensince quantitative clearance measurementsarenot possiblefor methodicalreasons.

V

toUNI HEIDELBERGNUKLEARMED IZ IN

.I KIDNEY FUNCTION

40.0 MBq

Tc -99m-MAG3

POST (upright)

.Relat. Parameters:

left (S'.] : 39.00

right (S'.] : 61.00

C1.—Irsdex : 31.40

2—3mm 3—4mth

I.4-5 mm 7—@mmn 9—@mmn

1.

left kidney

right kidney

—. —. — background

14—*snin

(1/2 t@ensIty) —bmmn

18— mm 19

27 Sen 1989 at 13:49

1291Pharmacokinetics of Technetium-99m-MAG3 in Humans •Bubeck et al

post m@ttonem(supine)

substances in the tubular cell must be involved.―The lattercould again be explained by different affinities to the tubulartransport system, as has been shown for OIH and @mTc@MAO3in the presentpaper.

ACKNOWLEDGMENT

The authors thank Mrs. Dorina Mack for her excellenttechnical assistance in the renal clearance studies.

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