Monitoring Nonsurgical and Surgical Root Canal Treatment of Teeth with Primary and Secondary Infections

The aim of this study was to monitor nonsurgical and surgical root canal treatment (RCT) of teeth with primary and secondary infections and apical periodontitis (AP). This prospective clinical study comprised the treatment of 80 patients with primary and persistent secondary infections and AP. Of this initial sample, forty patients did not return. Periapical index using cone beam computed tomography scans (CBCTPAI) was used to aid diagnosis, planning and to determine the better therapeutic strategy. Twenty patients (26 teeth) diagnosed with primary infection and AP received conventional RCT and were followed up for 10 to 36 months. Twenty patients (31 teeth) diagnosed with persistent secondary infection were submitted to periapical surgical and followed up for 6 to 30 months. The results showed RCT successful in 19/26 cases with complete AP healing (5/26 with partial repair) in 10-36 months of follow up. For the surgically managed cases, effectiveness of surgical therapy was detected in 10/31 cases with complete healing (10/31 cases with partial repair) within 6-30 months follow up. The return of patients for clinical and radiographic follow-up, and obedience to the proposed time period was very short from ideal. The levels of success in both therapeutic protocols were high. RCT failures were detected even with rigorous standard clinical protocols.

O objetivo do estudo foi monitorar tratamentos de canais radiculares (TCR) convencionais e com auxílio de cirurgia periapical. Este estudo prospectivo constituiu de 80 pacientes portadores de infecções primárias e secundárias persistentes e periodontite apical (PA). O índice periapical utilizando tomografia computadorizada de feixe cônico (CBCTPAI) foi utilizado como auxiliar no diagnóstico, planejamento e para determinar a melhor estratégia terapêutica. Apenas 40 pacientes retornaram para o TCR. Em 20 pacientes (26 dentes) com diagnósticos de infecções primárias e PA foram feitos TCR convencionais e monitoramentos por 10 a 36 meses. Em 20 pacientes (31 dentes) com diagnósticos de infecções secundárias persistentes foram submetidos a procedimentos cirúrgicos e acompanhamentos durante 6 a 30 meses. Os resultados mostraram TCR bem sucedidos em 19 de 26 casos, com curas completas das PA (5 de 26 com reparação parcial) em controles de 10 a 36 meses. Para os casos de tratamentos cirúrgicos foram detectadas eficácias das terapêuticas cirúrgicas em 10 de 31 casos com curas completas (10 de 31 casos com reparação parcial) em controles de 6 a 30 meses. O retorno dos pacientes para controle clínico e radiográfico e a obediência ao período de tempo proposto está muito aquém do ideal. Os níveis de sucesso em ambos os protocolos terapêuticos se mostraram elevados. Fracassos no TCR foram detectados mesmo utilizando protocolo clínico com rigoroso padrão.

Preclinical evaluation of 99mTc(CO)3-aspartic-N-monoacetic acid, a renal radiotracer with pharmacokinetic properties comparable to 131I-o-iodohippurate.

UNLABELLED: In an ongoing effort to develop a renal tracer with pharmacokinetic properties comparable to p-aminohippurate and superior to those of both (99m)Tc-mercaptoacetyltriglycine and (131)I-o-iodohippurate ((131)I-OIH), we evaluated a new renal tricarbonyl radiotracer based on the aspartic-N-monoacetic acid (ASMA) ligand, (99m)Tc(CO)(3)(ASMA). The ASMA ligand features 2 carboxyl groups and an amine function for the coordination of the {(99m)Tc(CO)(3)}(+) core as well as a dangling carboxylate to facilitate rapid renal clearance. METHODS: rac-ASMA and l-ASMA were labeled with a (99m)Tc-tricarbonyl precursor, and radiochemical purity of the labeled products was determined by high-performance liquid chromatography. Using (131)I-OIH as an internal control, we evaluated biodistribution in normal rats with (99m)Tc(CO)(3)(ASMA) isomers and in rats with renal pedicle ligation with (99m)Tc(CO)(3)(rac-ASMA). Clearance studies were conducted in 4 additional rats. In vitro radiotracer stability was determined in phosphate-buffered saline, pH 7.4, and in challenge studies with cysteine and histidine. (99m)Tc(CO)(3)(ASMA) metabolites in urine were analyzed by high-performance liquid chromatography. RESULTS: Both (99m)Tc(CO)(3)(ASMA) preparations had greater than 99% radiochemical purity and were stable in phosphate-buffered saline, pH 7.4, for 24 h. Challenge studies on both revealed no significant displacement of the ligand. In normal rats, the percentage injected dose in urine at 10 and 60 min for both preparations averaged, respectively, 103% and 106% that of (131)I-OIH. The renal clearances of (99m)Tc(CO)(3)(rac-ASMA) and (131)I-OIH were comparable (P = 0.48). The tracer was excreted unchanged in the urine, proving its in vivo stability. In pedicle-ligated rats, (99m)Tc(CO)(3)(rac-ASMA) had less excretion into the bowel (P < 0.05) than did (131)I-OIH and was better retained in the blood (P < 0.05). CONCLUSION: Both (99m)Tc(CO)(3)(ASMA) complexes have pharmacokinetic properties in rats comparable to or superior to those of (131)I-OIH, and human studies are warranted for their further evaluation.

99mTc(CO)3-nitrilotriacetic acid: a new renal radiopharmaceutical showing pharmacokinetic properties in rats comparable to those of 131I-OIH.

UNLABELLED: To develop a (99m)Tc renal tracer with a capacity to measure effective renal plasma flow comparable to that of the clinical gold standard (131)I-o-iodohippurate ((131)I-OIH) and superior to that of (99m)TcO-mercaptoacetyltriglycine, which has a clearance only 50%-60% that of (131)I-OIH, we investigated (99m)Tc-tricarbonyl nitrilotriacetic acid (Na(2)[(99m)Tc(CO)(3)(NTA)]). This radiopharmaceutical, which is based on an aminopolycarboxylate ligand, is formed as a single species and has a dangling carboxylate group favoring tubular transport. METHODS: Na(2)[(99m)Tc(CO)(3)(NTA)] was prepared by using commercially available NTA and an IsoLink kit and isolated by high-performance liquid chromatography. The stability of Na(2)[(99m)Tc(CO)(3)(NTA)] in isotonic saline was assessed for 24 h and was further evaluated by incubation in 0.1 M cysteine and histidine for 4 h at 37 degrees C. The biodistribution of Na(2)[(99m)Tc(CO)(3)(NTA)], coinjected with (131)I-OIH as an internal control, was evaluated in 5 normal Sprague-Dawley rats at 10 min, 5 normal Sprague-Dawley rats at 60 min (group A), and 6 rats with renal pedicle ligation at 60 min (group B) after injection. Clearance and extraction fraction studies were conducted in 2 normal Sprague-Dawley rats, and urine and plasma from 2 additional normal rats each were analyzed for metabolites by high-performance liquid chromatography. RESULTS: The radiochemical purity of Na(2)[(99m)Tc(CO)(3)(NTA)] was greater than 99%, the complex was stable for 24 h at physiologic pH, and the challenge experiments showed no degradation. In normal rats, the percentage dose in the urine at 10 and 60 min was 108% +/- 9% and 101% +/- 5%, respectively, that of (131)I-OIH; minimal hepatic or gastrointestinal activity was demonstrated. In group B rats, Na(2)[(99m)Tc(CO)(3)(NTA)] was better retained in the blood and had less excretion into the bowel than did (131)I-OIH (P < 0.01). The plasma clearances of Na(2)[(99m)Tc(CO)(3)(NTA)] and (131)I-OIH were comparable, but the extraction fraction of Na(2)[(99m)Tc(CO)(3)(NTA)] was 93.5% +/- 3.8%, compared with 67.9% +/- 6.1% for (131)I-OIH. Plasma protein binding of Na(2)[(99m)Tc(CO)(3)(NTA)] averaged 67% +/- 7%, and red cell uptake was 7% +/- 2%. CONCLUSION: Na(2)[(99m)Tc(CO)(3)(NTA)] is stable, exists as a single species, and has pharmacodynamic properties in rats comparable to those of (131)I-OIH.

Effect of protein binding on renal extraction of 131I-OIH and 99mTc-labeled tubular agents.

UNLABELLED: The clearance of 99mTc-mercaptoacetyltriglycine (MAG3) is less than the clearances of o-131I-iodohippurate (OIH) and 99mTc-labeled DD- and LL-ethylenedicysteine (EC). This difference could be associated with the lower affinity of MAG3 for the tubular transport receptor, but MAG3 is more highly protein bound than OIH and the EC isomers; protein binding could also be an important factor governing tubular extraction. To separate the effects of protein binding from tubular receptor affinity, the extraction fractions (EFs) of MAG3, OIH, and the DD, LL, and DL isomers of 99mTc-EC were measured in an isolated perfused rat kidney model using a protein-free perfusate and perfusates containing bovine serum albumin. METHODS: The right kidney was removed from the rat and perfused with modified Krebs-Henseleit buffers containing 7.5 or 2.5 g/dL bovine serum albumin or a protein-free perfusate. OIH was coinjected into the renal artery with each of the 99mTc-tracers. Protein binding was measured in each of the perfusates, and the venous outflow was collected to determine the EF. RESULTS: The protein binding of MAG3 in the albumin perfusates ranged from 87% to 95%, significantly higher than the 20%-34% range of protein binding observed with the three EC complexes (P < 0.05). In the 2.5 g/dL albumin perfusate, the EF of MAG3 was 44%, significantly less than the 57%-77% EF of the three EC complexes; in the 7.5 g/dL perfusate, the MAG3 EF fell to 18% versus 39%-45% for the EC complexes (P < 0.05). However, in the protein-free perfusate, the EF of MAG3 was 64%, equal to or higher than the 46%-62% EF of the three EC complexes. CONCLUSION: Protein binding modulates the tubular extraction of renal tracers. Protein binding and receptor affinity must be considered in the design of future renal radiopharmaceuticals as well as radiopharmaceuticals targeting other receptors.

Clearance and renal extraction of technetium-99m-L,L-ethylenedicysteine, I-131-ortho-iodohippurate and I-125-iothalamate in pigs.

99mTc-L,L-ethylenedicysteine (99mTc-EC) has been proposed as a 99mTc-labelled alternative to radio-iodinated ortho-iodohippurate (OIH) for renal imaging and evaluation of renal function. The kinetics of this new renal function agent were studied by a single-injection plasma clearance technique in pigs. 99mTc-EC, 131I-OIH and 125I-iothalamate were injected and the plasma concentration of the three tracers was followed for 240 min. Renal, hepatic and total plasma clearance were calculated. There was no difference between the renal plasma clearance of 99mTc-EC and 131I-OIH (175 +/- 9 versus 178 +/- 8 ml min-1, P = 0.43), whereas the difference between the total plasma clearance of 99mTc-EC and 131I-OIH was highly significant (268 +/- 16 versus 185 +/- 9 ml min-1, P = 0.0001). 99mTc-EC had a significant hepatic clearance of 83 +/- 10 ml min-1 whereas the hepatic clearance of 131I-OIH was negligible. Renal plasma extraction of both 99mTc-EC and 131I-OIH decreased significantly between 2 and 240 min post-injection from 0.85 to 0.45% for 99mTc-EC and from 0.93 to 0.57% for 131I-OIH. Red blood cell binding of 99mTc-EC and 131I-OIH was 6.1% and 20%, respectively. The protein binding of 99mTc-EC and 131I-OIH was 32% for both tracers. We conclude that 99mTc-EC is not a suitable tracer for measuring renal function by the single-injection plasma clearance technique in pigs. This is due to a decreasing renal extraction and a significant hepatic clearance.

Assessment of the radiochemical design of antibodies with a metabolizable linkage for target-selective radioactivity delivery.

Interposition of a metabolizable linkage has been performed to reduce the hepatic radioactivity levels of radiolabeled antibodies. To estimate the validity of this strategy, a radioiodination reagent (HML) that provides a stable attachment for m-iodohippuric acid with proteins in plasma while facilitating rapid and selective release of the compound after lysosomal proteolysis in the liver was conjugated with a monoclonal antibody (mAb) against osteogenic sarcoma (OST7, IgG1). Radiolabeled OST7 conjugates with a plasma-labile ester bond for releasing m-iodohippuric acid (MIH), plasma-stable amide bonds for releasing radiometabolites of hepatobiliary excretion (MPH), or slow elimination rates from hepatocytes ([111In]EMCS-Bz-EDTA) were prepared with similar conjugation chemistry. The four radiolabeled OST7 conjugates were characterized both in vitro and in vivo. All the radiolabeled OST7 conjugates had similar radiochromatograms on size-exclusion HPLC and similar antigen binding affinities. While MIH-OST7 indicated accelerated clearance of radioactivity from the blood due to the release of m-iodohippurate, the rest of the three radiolabeled OST7 conjugates remained stable in serum incubation studies and had similar radioactivity elimination from the blood in vivo. When injected into normal mice, HML-OST7 demonstrated tissue-to-blood ratios of radioactivity similar to those of MIH-OST7 and significantly lower than those of the other two radiolabeled OST7 conjugates. In biodistribution studies in nude mice, both HML-OST7 and MIH-OST7 exhibited tumor-to-liver or tumor-to-intestine ratios of radioactivity higher than those of [111In]EMCS-Bz-EDTA-OST7 or MPH-OST7, respectively. HML-OST7, MPH-OST7, and [111In]EMCS-Bz-EDTA-OST7 indicated there were no changes in the radioactivity levels in the tumor between 24 and 48 h postinjection, whereas MIH-OST7 significantly decreased the radioactivity levels in the tumor at these time points. HML reduced the radioactivity levels in nontarget tissues without impairing the tumor radioactivity levels delivered by OST7. These findings indicated that the design of a radiolabeled mAb that is stable in plasma and liberates the radiometabolite of rapid urinary excretion constitutes an effective strategy for achieving target-selective radioactivity delivery.

Evaluation of 99Tcm-bicisate as a renal imaging agent.

99Tcm-bicisate (99Tcm-ECD), often used as a brain perfusion agent, is rapidly converted following intravenous injection to the polar monoacid (99Tcm-ECM) and diacid (99Tcm-EC) metabolites. Such polar metabolites, which are eliminated principally by renal clearance, are potential renal imaging agents. In this study, 99Tcm-ECD was compared for the first time with 99Tcm-EC, 99Tcm-mercaptoacetyltriglycine (99Tcm-MAG3) and 131I-orthoiodohippurate (OIH) as renal imaging agents in rabbits. Whole-body images and renograms were obtained for all three of the 99Tcm agents, and pharmacokinetic parameters including plasma and urinary clearance were studied for all four agents. The plasma clearance of 99Tcm-EC (37 ml min-1) was slower than that of 99Tcm-ECD (51 ml min-1), which could be accounted for by the higher liver uptake of 99Tcm-ECD. The urinary clearance of 99Tcm-ECD (35 ml min-1), 99Tcm-EC (34 ml min-1) and 99Tcm-MAG3 (39 ml min-1) was similar. The renal images obtained with 99Tcm-ECD were comparable to those for 99Tcm-MAG3 and 99Tcm-EC. However, liver uptake was more prominent with 99Tcm-ECD than with the other agents. The 99Tcm-ECD renogram curves showed a prolonged decrease in renal activity compared to both 99Tcm-EC and 99Tcm-MAG3. In potential human studies, the relatively high liver uptake of 99Tcm-ECD superimposed on right renal activity may be a limitation. Therefore, we conclude that 99Tcm-ECD is less favourable when compared to existing renal agents due to its high extrarenal uptake and renal kinetics.

Technetium-99m L,L-ethylenedicysteine clearance and correlation with iodine-125 orthoiodohippurate for the determination of effective renal plasma flow.

Technetium-99m L,L-ethylenedicysteine (99mTc-L,L-EC) is a new renal tubular tracer that allows the determination of the effective renal plasma flow (ERPF). The aim of this study was to derive simplified methods for the estimation of 99mTc-L,L-EC clearance using one or two plasma samples after bolus injection. Fifty-nine multiple plasma dual-tracer samples (nine samples from 5 to 120 min after injection) were obtained after injection of kit-formulated 99mTc-L,L-EC and iodine-125 orthoiodohippurate (OIH). The studies were performed in 25 stable and 24 unstable transplant recipients, in five patients with renal insufficiency (four on chronic haemodialysis) and in five normal volunteers. This allowed a wide range of renal function values to be covered, with ERPF (estimated by OIH clearance) ranging from 25.4 to 604.0 ml/min. The reference 99mTc-L,L-EC clearance, as calculated from the multisample model, could be estimated from two samples at 15 and 90 min with an error of 11.3 ml/min and from one sample at 90 min with an error of 17.8 ml/min. Using appropriate linear regression analysis, ERPF could be estimated by the two- and one-sample 99mTc-L,L-EC clearance with an error of 24.2 and 22.8 ml/min, respectively. In conclusion, 99mTc-L,L-EC clearance can be accurately estimated by simplified one- or two-sample methods. Moreover, these methods can be used to estimate ERPF with an error that remains acceptable for clinical purposes.

Clinical comparison of technetium-99m-EC, technetium-99m-MAG3 and iodine-131-OIH in renal disorders.

UNLABELLED: Technetium-99m-ethylenedicysteine has recently been developed for renal function studies. The pharmacokinetics of 99mTc-EC were studied by constant infusion technique and compared with 99mTc-MAG3 and 131I-OIH in 11 patients with various renal disorders. METHODS: After giving a 7.4 MBq 131I-OIH and 90-110 MBq 99mTc-EC or 99mTc-MAG3 bolus, a constant infusion (1MBq/ml 99mTc-agent and 0.07 MBq/m 131I-OIH was started. Sixteen blood and five urine samples were obtained over three hr. RESULTS: The renal clearance of 99mTc-EC was higher than that of 99mTc-MAG3. The 99mTc-EC/OIH and 99mTc-MAG3/OIH ratios were 0.75 +/- 0.05 and 0.55 +/- 0.10 (p = 0.00087), respectively. The distribution volume of 99mTc-EC was also higher than that of 99mTc-MAG3 (15722 +/- 4644 and 9509 +/- 2788 ml/1.73m2, respectively; p = 0.072). The 99mTc-EC/OIH and 99mTc-MAG3/OIH distribution volume ratios were 1.03 +/- 0.14 and 0.55 +/- 0.10, respectively (p = 0.0003). The 60-min excretion values of 99mTc-EC and 99mTc-MAG3 were compared to that of OIH. The 99mTc-EC/OIH and 99mTc-MAG3/OIH excretion ratios were 0.96 +/- 0.06 and 1.07 +/- 0.10, respectively (p = 0.162). The protein binding of 99mTc-EC and OIH were found to be 34% +/- 4 and 66% +/- 5, respectively (p < 0.0001). The red cell binding of 99mTc-EC was negligible (3% +/- 1.2) in comparison to OIH (27% +/- 3; p < 0.0001). CONCLUSION: This limited study demonstrates the pharmacokinetic and renal clearance properties of 99mTc-EC. This agent has good potential for renal function evaluation.

Evaluation of technetium-99m-L,L-EC in renal transplant recipients: a comparative study with technetium-99m-MAG3 and iodine-125-OIH.

UNLABELLED: The clinical usefulness of kit-formulated 99mTc-L,L-EC, a new renal tubular tracer agent based on a diaminodithiol ligand was evaluated in a large population of renal transplant recipients. METHODS: Fifty patients with transplants were studied. Five patients with renal insufficiency and five normal volunteers were also included to extend the range of renal function values. The labeling efficiency of 99mTc-L,L-EC in routine conditions, i.e., without HPLC purification, and the safety of the tracer were evaluated. RESULTS: The mean radiochemical purity of 99mTc-L,L-EC determined by thin-layer chromatography was 97.4%. No side effects or significant biochemical changes were observed. The clearance of 99mTc-L,L-EC and 125I-OIH ranged from 10.7 to 417.5 and from 27.6 to 602.7 ml/min/1.73 m2, respectively. The clearance of 99mTc-L,L-EC and 99mTc-MAG3 averaged respectively 71% and 52% of that of 125I-OIH. CONCLUSION: The labeling procedure of kit-formulated 99mTc-L,L-EC is easy and efficient. This tracer is safe and suitable for both imaging and quantitative measurement of the renal tubular function. Technetium-99m-L,L-EC represents an excellent alternative to 99mTc-MAG3.

99Tcm-cystine, a renal function and imaging agent: a comparative study in dog with 131I-hippurate and 99Tcm-glucoheptonate to evaluate its functional and imaging characteristics.

99Tcm-cystine, which has been proposed as a renal radiopharmaceutical for evaluating renal morphology and function in a single experiment, is compared with 131I-orthoiodohippurate (OIH) with respect to its renal clearance and extraction parameters and with 99Tcm-glucoheptonate (GHA) regarding its imaging characteristics. In spite of its comparable renal accumulation with 131I-OIH, its clearance (10.1 +/- 1.0 ml min-1 kg-1) was lower than that of 131I-OIH (21.5 +/- 0.9 ml min-1 kg-1) but was higher than that of 125I-iothalamate (5.4 +/- 0.6 ml min-1 kg-1). Extraction efficiencies of 99Tcm-cystine, 131I-OIH and 125I-iothalamate were 39 +/- 5, 64 +/- 4 and 27 +/- 3, respectively. The glomerular filtration components of 99Tcm-cystine and 131I-OIH were 26 and 16% of their respective clearances. In probenecid-treated animals the clearance of both agents was affected to a similar extent and fell to half of their respective control values, whereas tubular secretory components were found to be 19 and 31% of the controls. The kidney images obtained with 99Tcm-cystine were superior to those obtained with 99Tcm-GHA at different time points. Therefore, considering both renal function and imaging properties of 99Tcm-cystine it appears that this radiopharmaceutical offers some definite advantages over the currently available renal agents and commands further study.

Radiation dosimetry for technetium-99m-MAG3, technetium-99m-DTPA, and iodine-131-OIH based on human biodistribution studies.

Radiation dose estimates were calculated for the renal agents 99mTc-DTPA, 99mTc-MAG3, and 131I-OIH from biodistribution data gathered in groups of healthy human volunteers. Biokinetics were evaluated by Anger camera imaging, blood sampling, and urine collection and counting. Collected data were fit to four- or five-compartmental models using the CONversational Simulation, Analysis, and Modeling (CONSAM) software. Radiation dose estimates were performed using standard MIRD techniques. Average residence times in urinary bladder, kidney, and remainder of the body were used to predict radiation dose equivalents and effective dose equivalents for the three agents. Doses for DTPA and MAG3 were very similar and much lower on a per unit injected activity than OIH. The effective dose equivalents were 3.3 mSv/370 MBq for 99Tc-DTPA, 3.7 mSv/370 MBq for 99mTc-MAG3, and 0.99 mSv/11.1 MBq for 131I-OIH for bladder voiding every 4.8 hr; effective dose equivalents were 2.0 mSv/370 MBq for 99mTc-DTPA, 1.5 mSv/370 MBq for 99mTc-MAG3, and 0.28 mSv/11.1 MBq for 131I-OIH for bladder voiding at 30 min and then every 4.0 hr. Patients should void at the conclusion of the study, as early voiding can reduce the gonadal radiation dose by a factor of 2 to 3.

Pharmacokinetics of technetium-99m-MAG3 in humans.

Technetium-99m-mercaptoacetylglycylglycylglycine (99mTc-MAG3) is introduced to replace o-iodohippurate (OIH) for renal function studies. For interpretation of clinical findings, extensive pharmacokinetic studies were performed on patients. These showed that 99mTc-MAG3, compared with OIH, has a higher plasma-protein binding, an essentially higher intravascular concentration, a smaller volume of distribution and, with practically identical biologic half-lives, a correspondingly lower clearance. Simultaneous steady-state measurements resulted in a 1.5-fold higher clearance of OIH than of 99mTc-MAG3 (n = 124). Competitive inhibition of the tubular transport system by p-aminohippurate (PAH) (20 patients) revealed a distinctly higher suppression of the 99mTc-MAG3 clearance than of OIH which indicates a lower affinity of the 99mTc complex to the tubular cell. The plasma extraction efficiencies of both agents, measured during surgery (n = 5), did not indicate an extrarenal elimination of 99mTc-MAG3. This new radiopharmaceutical is a pragmatic alternative to OIH and offers advantages not only for scintigraphic imaging but is also suited for quantitative renal function studies.

Effects of altered physiologic states on clearance and biodistribution of technetium-99m MAG3, iodine-131 OIH, and iodine-125 iothalamate.

Technetium-99m mercaptoacetyltriglycine [( 99mTc]MAG3) is a new renal radiopharmaceutical with biologic properties similar to iodine-131 orthoiodohippuric acid [( 131I]OIH). MAG3 may be used as a replacement for [131I]OIH and/or [99mTc]DTPA. For this reason, we compared the effects of several potential adverse clinical conditions on the clearance and biodistribution of MAG3, OIH and a GFR marker. To simulate renal failure, five mice underwent bilateral renal pedical ligation. Twenty-four hours after surgery they were injected with MAG3 and OIH and killed 2 hr postinjection. Compared to sham operated controls, liver activity for MAG3 and OIH increased from 0.2% to 14.1% and 0.1% to 13.9%, respectively, while intestinal activity increased from 1.3% to 8.9% for MAG3 and 0.2% to 7.7% for OIH. Constant infusion studies were performed in rats to evaluate the effects of increased plasma organic acid levels, mannitol diuresis, dehydration, and acid/base imbalance on the clearance of OIH, MAG3, and [125I]iothalamate. No differences were noted between the OIH and MAG3 clearances following diuresis and dehydration and the differences involving acid/base imbalance were minimal. Dehydration depressed the clearance of [125I]iothalamate more than that of OIH or MAG3. Para-aminohippurate (PAH) infusion inhibited the clearance of MAG3 more than OIH supporting proximal tubular transport for MAG3; PAH had no effect on [125I]iothalamate. In summary HPLC purified MAG3 behaved similarly to OIH under adverse physiologic conditions and the data continue to support the use of MAG3 as a potential clinical substitute for OIH.