Technetium-99m-mercaptoacetyltriglycine (^99mTc-MAG₃) is a radiopharmaceutical for renal tubular function that has been used for several years replacing the traditional radio-iodinated orthoiodohippurate (¹³¹I-OIH), because of the excellent radionuclidic properties of technetium-99m in comparison with iodine-131. The clearance of ^99mTc-MAG₃ corresponds to the tubular extraction rate (TER), but its value is only 50–60% that of ¹³¹I-OIH, and, if the clearance is quantitatively measured, it could be an indicator of the effective renal plasma flow (ERPF), even though it does not provide a direct measure of either ERPF or GFR.

Vargas, in 1997, compared these two radio pharmaceuticals for ERPF determination in Mexicans. For the ^99mTc-MAG₃ studies in patients without renal illness, he used the gammacamera acquisition protocol with no blood samples, and the Schlegel formula for regions of interest on the images. For the ¹³¹I-OIH studies in the same patients, the Diethelm-Tauxe’s one-plasma-sample method was used. He reported similar values: ERPF = 482 ± 92 ml/min with ^99mTc-MAG₃ and 490 ± 69 ml/min with ¹³¹I-OIH.

There are several methods to measure ^99mTc-MAG₃ clearance by using constant infusion or by single bolus injection and with a single blood sample or several blood samples. In all cases, the data can be fitted to a one-, two-, or no-compartment model of distribution. Also, with regions of interest drawn on the renal images from the gamma-camera, time/activity curves are obtained showing renal concentration and elimination.

It has been reported that the single- and multi-sample clearance methods give similar results. The former is usually used for routine clinical studies. The latter method implies the withdrawal of several blood samples, and is probably more accurate than necessary for most clinical situations and, because of its accuracy, is used for determining radiopharmacokinetic parameters. It requires 8 to 10 blood samples drawn at different time intervals after the substance of interest is injected. The cpm determined in each sample is plotted against time on semi-logarithmic graph paper. Generally, there is a rapid plasma disappearance curve during the first moments post-injection, after which the plasma concentration curve becomes less steep. From the graph of the two curves, the following data can be calculated: the slope (fast and slow), the intercept on the ordinate axes of both extrapolated plasma disappearance curves, and the area under the curve (AUC). These data determine the distribution and the pharmacokinetic parameters of the agent. The calculation is made easier by computer programs designed to represent the best model of distribution, be it compartmental or otherwise. In all models, the agent is injected into a first compartment, from which it is cleared, and which includes blood and spaces outside the blood. The agent’s distribution throughout the body is represented by a two-, three- or multiple-compartment model.

The single-sample clearance method is easier to perform, is quite precise, is convenient for clinical use and additionally, it has an advantage in that it can be done while acquiring a renal scan with a gammacamera. This one sample is assumed to fit to a known exponential function, according to the Tauxe equation.

In 1995, at the Instituto Nacional de Investigaciones Nucleares (ININ) in Mexico, an alkaline freeze-dried kit (pH 9) of benzoyl-protected mercaptoacetyltriglycine (Bz-MAG₃) was developed. Each vial contains 1.0 mg of the ligand Bz-MAG₃, 15 mg sodium gluconate and 0.1 mg anhydrous stannous chloride.

The ^99mTc-radiopharmaceutical prepared with the ININ kit does not have to be HPLC-purified before use; the radiochemical purity of ^99mTc-MAG₃ determined by ITLC or paper chromatography is >98%, plasma protein binding 89% 1 h post-injection, and 95.7% of the injected dose was secreted in the urine with minimal accumulation (0.4%) in the gastrointestinal and hepatobiliary systems of mice. In the rabbit scans, the gallbladder was not visualized.

Values for radiopharmacokinetic parameters found in the medical literature were those reported by Taylor and Bubeck. In a study with eight normal male volunteers, Taylor reported that 73% of the ^99mTc-MAG₃, prepared with a kit, was eliminated in the urine after 30 min, and 99.9% after 3 h. The radiopharmacokinetic parameters reported are the following: 0?60 min clearance = 340 ml/min (288 ± 53 ml/min/1.73 m²), and 4.4 ± 0.8 l volume of distribution V_d. In a previous study, this clearance value was 420 ± 120 ml/min for the same time interval and with HPLC-purified ^99mTc-MAG₃.

Bubeck, in 1990, in a comparative study of ^99mTc-MAG₃ with ¹³¹I-OIH in 14 renal patients and using Sapirstein’s formula for a two-compartment model, reported for ^99mTc-MAG₃ the following radiopharmacokinetic parameters: (a) plasma protein binding; (b) 0 to 30 min clearance; (c) slow elimination constant b₁; (d) slow half-life T_B; (e) fast elimination constant b₂; (f) fast half-life T_A, and (g) volume of distribution Vd₁ and Vd₁ + Vd₂.

For the Mexican population, no reports were found on radiopharmacokinetic or clearance studies in normal subjects with ^99mTc-MAG₃ prepared with either the Mexican-made or foreign Bz-MAG₃ kits, even though the Mexican kit is used for functional renal studies in at least 10 nuclear medicine centers throughout the country.

The main objective of this work was to determine, in healthy Mexican volunteers, several radiopharmacokinetic parameters of ^99mTc-MAG₃, prepared with the Bz-MAG₃ kit produced at ININ, Mexico, and to compare the clearance values determined with a single-sample method and the elaborate multi-sample methods.

Results

The values for the radiopharmacokinetic parameters calculated with all of the 0–43 min samples using the BIEXP program are listed in. The ^99mTc-MAG₃ was rapidly distributed in the central compartment with an apparent volume Vdcc = 3.8 ± 0.7 l and the steady state apparent volume of distribution Vdss = 6.7 ± 1.0 l. The uncorrected clearance at this time was 198 ± 50.2 ml/min. Each molecule had a mean retention time (MRT) of 0.60 ± 0.17 h and it was eliminated in the urine.

The values for Vdss and MRT calculated with all the plasma samples obtained at 0–4 h post-injection for a two-compartment model (BIEXP) and for a noncompartment model (CHAN) are shown in Pearson’s correlation for Vdss was r = 0.73 (t = ?1.4, p = 0.1), and for MRT: r = 0.99, t = ?3.87, and p = 0.004.

The clearance values calculated and corrected for the 1.73 m² body surface with the multi-sample method (6–8 plasma samples collected at 0–43 min post-injection) with the BIEXP program, with the single-sample method (43 min), and using Tauxe’s formula are listed. Correlation of calculated clearance obtained with both methods was r = 0.9 (t = 1.4, p = 0.11)

The mean clearance value obtained from all of the 0–4 h post-injection plasma samples, using Sapirstein’s formula, was 162 ± 44 ml/min, and the correlation with the 24-h urine creatinine clearance values of 137 ± 37 ml/min was r = 0.36, (t = 1.4, p = 0.2).

The total activity A in cpm of the accumulated 3-h urine sample was used for calculating (a) mean urine elimination = 67% ± 18%, and (b) mean renal clearance, with the formula Clr = A/AUC, was Clr = 91 ± 30 ml/min.

The data for the estimated absorbed radiation dose to several organs obtained with the MIRDOSE 3 program