Animal studies have suggested that 99mTc-mercapto-acetylglycyl-glycyl-glycine (99mTc-MAG3) might be suitable for the determination of the renal plasma flow (RPF) because of its high renal clearance. In this study 131I-orthoiodohippurate (131I-OIH) and 99mTc-MAG3 (labeling always greater than 95%) were administered simultaneously in 11 patients (creatinine clearance ranging from 14 to 130 ml/min per 1.73 m2) to measure effective RPF(ERPF) using the standard technique (UV/P). Glomerular filtration rate (GFR; clearance of 125I-thalamate, 125I-OT) was also measured. The mean ratio of 99mTc-MAG3 clearance to 131I-IOH clearance was 0.55 +/- 0.02 (SEM), P less than 0.01, n = 16, and was independent of GFR and ERPF. To study this difference in renal handling of the radiopharmaceuticals, renal extractions by the right kidney were determined in another six patients after a single shot of the agents. Renal extraction of 99mTc-MAG3 was 0.60 +/- 0.03 after 5 min, and 0.41 +/- 0.08 after 30 min. Renal extraction of 131I-OIH amounted to 0.86 +/- 0.04 and 0.77 +/- 0.03, respectively. Using renal extractions of 0.41 and 0.77, respectively, it appeared that calculated renal plasma flows measured simultaneously with 99mTc-MAG3 and 131I-OIH were similar. Protein binding 30 min after the priming dose was 66% for 99mTc-MAG3 and 47% for 123I-OIH. We conclude that in spite of a high renal clearance (ratio to 125I-OT clearance 2.69 +/- 0.27), 99mTc-MAG3 seems unsuitable for an accurate determination of the RPF.(ABSTRACT TRUNCATED AT 250 WORDS)