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Clinical Chemistry 43: 1429-1435, 1997;
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(Clinical Chemistry. 1997;43:1429-1435.)
© 1997 American Association for Clinical Chemistry, Inc.

Articles

Measurement of serum iohexol by determination of iodine with inductively coupled plasma–atomic emission spectroscopy

W. Emmett Braselton1,2,a, Kirk J. Stuart2 and John M. Kruger3

1 Departments of Pharmacology and Toxicology and
2 Small Animal Clinical Sciences, and
3 Animal Health Diagnostic Laboratory, College of Veterinary Medicine, Michigan State University, E. Lansing, MI 48824.
a Address correspondence to this author at: G302 Veterinary Medical Center, Michigan State University, E. Lansing, MI 48824. Fax (517) 355-2152; e-mail braselton{at}ahdlms.cvm.msu.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
We used inductively coupled plasma–atomic emission spectroscopy to measure serum iodine to determine plasma clearance of iohexol, an iodinated radiographic contrast agent. We determined I at 178.276 nm on the phosphorus 178.287 nm channel of the polychromator by utilization of spectrum shifter offset software, while correcting for P with the sequential P 214.914 nm emission line. Determination of I on the polychromator provided excellent precision in the measurement of serum I, even though the interelement correction of P was done with a sequential P line. Total imprecision (CV) (n = 13) was 16% (at 13.7 mg/L I), 8.6% (28.7 mg/L), 3.6% (59.0 mg/L), 2.6% (120.5 mg/L), 1.7% (237.8 mg/L), 1.2% (478.7 mg/L), and 1.8% (597 mg/L). The linear range was 15 to 600 mg/L. Iohexol added to serum (mg/L I) and recoveries (%) were 15 (91.3%), 30 (95.7%), 60 (98.3%), 120 (100.4%), 240 (99.1%), 480 (99.7%), and 600 (99.5%). Studies on dogs and cats administered a single intravenous injection of iohexol indicated that a dose of 300 mg I/kg body weight was sufficient for measurement of glomerular filtration rate by using a single compartment model for plasma clearance with three samples drawn 3 to 7 h after treatment. With this protocol, correlation coefficients were >0.99 on the ß phase of the plasma disappearance curve.


Key Words: indexing terms: glomerular filtration rate • iodine compounds • contrast media


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Iohexol is an iodinated radiographic contrast medium developed for use in diagnostic radiology. Because it is not protein bound and is totally excreted by the kidney through the process of glomerular filtration (1)(2), its clearance from plasma after a single injection can be used to estimate glomerular filtration rate (GFR) in humans and domestic animals (3)(4)(5)(6)(7)(8)(9).1 Several analytical methods have been developed for determination of iohexol concentrations in serum or plasma. The most commonly used procedure involves x-ray fluorescence (XRF) measurement of I (4)(5)(9)(10)(11)(12)(13) and has led to development of a commercial instrument (7)(8)(9)(13)(14)(15). XRF is convenient in its simplicity and capacity for rapid turnaround, which are important in the human clinical situation. Drawbacks to the XRF method include high cost, limited diagnostic applications, use of radioisotopes (241Am source), high detection limits, and relatively large sample requirements (4 to 6 mL of whole blood is recommended). Large sample size may become problematic in studies involving infants or small animals. Other methods described in the literature include a colorimetric method involving deiodination by alkaline hydrolysis and measurement of released I by the ceric arsenite method (16), HPLC with UV detection (3)(6)(17)(18)(19), and capillary electrophoresis (20)(21). The HPLC methods, although somewhat more sensitive, have not gained widespread use presumably because of the time and intricacies involved in setting up the method (16)(21). The colorimetric method becomes nonlinear above 120 mg/L, which is in the range seen with renal impairment. The capillary electrophoresis method is rapid and has low detection limits if preceded by acetonitrile deproteinization. However, two separate methods of sample preparation, calibration, and analysis are needed to achieve linearity in a low range and a high range that do not overlap, posing problems in covering the entire range of serum I that may be encountered in a diagnostic evaluation (20). Since inductively coupled plasma–atomic emission spectroscopy (ICP-AES) is becoming increasingly available in medical centers for a variety of applications, we describe here the development of an ICP-AES procedure to estimate GFR through determination of iohexol plasma clearance by the measurement of serum I. When compared with the XRF method, the ICP-AES method offers improved detection limits, allowing administration of lower doses of iohexol and collection of smaller serum samples for analysis, both of which are desirable in studies involving infants or small animals. The excellent accuracy, precision, and linearity achieved with the ICP-AES method in the range of I useful in clinical determination of GFR overcomes some of the limitations of other published methods.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
apparatus
Experiments were carried out on a Thermo Jarrell Ash Polyscan 61E Simultaneous/Sequential inductively coupled plasma–atomic emission spectrometer with vacuum spectrometers and Ar-purged optical paths (Thermo Jarrell Ash, Franklin, MA). The instrumental operating parameters and element wavelengths with corresponding detection limits are given in Table 1 . Other apparatus included class A volumetric flasks, acid washed; 1-mL serologic pipettes; Gilson Pippettman (Rainin Instrument Co., Woburn, MA) calibrated with water gravimetrically to deliver 0.200 ± 0.002 mL.


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  		Table 1. ICP-AES operational parameters.

reagents
Baker Instra-Analyzed hydrochloric acid (Baxter Diagnostics, Scientific Products Division, McGaw Park, IL); trichloroacetic acid (TCA), 99+% (GFS Chemicals, Powell, OH); Johnson Matthey ICP/DCP single element stock P solution, 10 000 mg/L (Johnson-Matthey/Aesar, Ward Hill, MA); hydroxylamine sulfate, 99+% (Aldrich Chemical Co., Milwaukee, WI); iohexol, 300 g I/L (Omnipaque® 300; Sanofi Winthrop Pharmaceuticals, New York, NY); bovine serum (Sigma Chemical Co., St. Louis, MO); 18 M{Omega} water from a Millipore 4 bowl purification system (Millipore Corp., Bedford, MA).

Iohexol solutions were prepared from the iohexol reference standard, which is 300 000 mg/L I, by a series of 1:10 dilutions in water.

Protein precipitation solution (PPTS) was prepared by combining 67.7 g of TCA, 35.0 g of hydroxylamine sulfate, and 140 mL of HCl in a 1000-mL volumetric flask containing ~500 mL of water. Reagents were dissolved and brought to volume with water.

ICP calibrators were made as follows: STD 1, blank: 10 mL of water was added to a 100-mL volumetric flask containing ~50 mL of PPTS, and brought to volume with PPTS. STD 2, 10 mg/L P: Into a 100-mL volumetric flask containing ~50 mL of PPTS was added 9.9 mL of water and 0.1 mL of stock P. The mixture was brought to volume with PPTS. STD 3, 10 mg/L I: Into a 100-mL volumetric flask containing ~50 mL of PPTS was added 9.7 mL of water and 0.333 mL of the 3000 mg/L iohexol supplementing solution. The mixture was brought to volume with PPTS.

To determine, on a daily basis, the correction of P on the I 178.276 line, an interelement correction solution containing 50 mg/L P was prepared by adding 0.95 mL of water plus 0.05 mL of stock P into a 10-mL volumetric flask and bringing to volume with PPTS. A second interelement correction solution containing 100 mg/L P was prepared by adding 0.90 mL of water plus 0.100 mL of stock P to a 10-mL volumetric flask and bringing to volume with PPTS. The percent interference of P on the 178.276 I line was determined with both solutions, and the average value used in the correction. Care was taken in the preparation of the calibrators and the interelement correction solution to have a final PPTS concentration of 90%, to match the matrix of the precipitated serum samples prepared below.

animals
Four adult dogs and one cat were studied (Table 2 ). Except for dog 2, all animals were pets presented to the Michigan State University Veterinary Teaching Hospital for diagnostic evaluation. Animal owners were briefed on the nature of the study and were asked to agree to the study following the ethical principles of informed consent. Dog 2 was obtained from the Michigan State University Laboratory Animals Resources Department. All animals were treated and maintained in accordance with the USDA and NIH guidelines for care and use of animals. Animal 1 received iohexol equivalent to 600 mg I/kg intraveneously as part of an excretory urogram to evaluate renal morphology. All other animals received 300 mg I/kg intravenously. Serial 3-mL venous blood samples were collected at intervals indicated in Table 2 . Total plasma clearance (ClT), t1/2{alpha}, and t1/2ß were calculated by the standard pharmacokinetic two-compartment open model (22) with least-squares regression analysis (SlideWrite® Plus Version 3 for WindowsTM; Advanced Graphics Software, Carlsbad, CA) to fit the biexponential function [C(t) = Ae-{alpha}t + Be-ßt] to the plasma iohexol concentration C(t) vs time (t) data, where A was the intercept of the distribution phase and B the intercept of the elimination phase at (t) = 0; {alpha} was the rate constant of the distribution phase and ß the rate constant of the elimination phase.


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  		Table 2. Species, breed, sex, and condition of study animals.

The plasma clearance was also calculated by using a one-compartment model (23), where data from the linear portion of the elimination phase, representing samples taken at 120 min or later, were fitted to a monoexponential function [C(t) = Be-ßt] where C(t) was the plasma concentration of I at a given time (t), B was the intercept of the curve at (t) = 0, and ß was the rate constant of the curve. The final pharmacokinetic parameters were calculated from the equations AUC = B/ß, Cl1c = D/AUC, and t1/2ß = ln2/ß

Note that Bröchner-Mortensen (23) applied a correction factor after calculation of Cl1C that was derived from human data to account for the overestimation of plasma clearance by the one-compartment model, which ignores the AUC of the distribution phase. The correction factor has not been proven to be applicable to canine or feline data to date because of a lack of experimental data obtained under both one- and two-compartment models. Therefore the Bröchner-Mortensen correction factor was not applied in the current experiments.

The plasma clearances were then adjusted for the animal weight and expressed as GFR-1c or GFR-2c (one- or two- compartment models) with the units mL min-1 kg-1.

sample preparation
Recovery and linearity.
Bovine serum in 1.0-mL aliquots was pipetted into individual 15-mL disposable conical centrifuge tubes and an appropriate volume of iohexol serum supplementing solution was added to give final concentrations of 0, 15, 30, 60, 120, 240, 480, and 600 mg/L I.

Animal serum samples.
Blood was collected from treated animals at intervals indicated in Table 2Up . Serum was collected by centrifugation and stored at -20 °C. Aliquots (1-mL) of the thawed serum were pipetted into 15-mL disposable conical centrifuge tubes for analysis.

Protein precipitation of serum additions and samples.
Serum was prepared for ICP-AES analysis by a procedure routinely used in veterinary diagnostic laboratories for serum element analysis (24). PPTS (9.0 mL) was added to each 15-mL conical centrifuge containing serum (with or without added I). The tube was covered with Parafilm, inverted several times, and centrifuged for 10 min at 1430g. Aspiration into the nebulizer was direct from the supernatant to avoid remixing of the protein precipitate by decantation.

determination
The ICP was operated according to parameters given in Table 1Up . PPTS was introduced into the nebulizer for at least 30 min before calibration to minimize instrument drift. The instrument was calibrated with STD 1, STD 2, and STD 3. The interelement correction solutions were analyzed as unknowns and the average value of the percent P interference on I calculated. Sera with and without added I were interspersed before analysis. Calibrators were checked after every 10 samples, and recalibration performed if drift was >± 2%.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
measurement of i at 178.276 nm
Choice of I emission line.
To estimate GFR by using iohexol plasma clearance after a single injection, a limit of quantification of I in serum of 20 mg/L or less was anticipated to be necessary. Manufacturer-provided wavelength tables indicated that two I emission lines are potentially intense enough to allow measurement of I at this sensitivity, the second-order lines at 178.276 nm and 183.038 nm, with instrument detection limits of ~0.050 and 0.20 mg/L respectively. Preliminary trials with the sequential spectrometer indicated that only the 178.276 line would provide satisfactory precision at the concentrations in serum required. Unfortunately, this line has a major interference from the P line at 178.287 nm, with P present in canine serum samples at 20–70 mg/L. The closeness of the two lines in fact precluded reliable peak identification of I by the sequential peak centroid algorithm at low serum I concentrations. Experiments were then conducted to measure I in the P 178.287 nm channel of the fixed polychromator, with a peak offset algorithm to reproducibly center the top of the I 178.276 nm emission line. Fig. 1 shows the wavelength scans of 10 mg/L P and 10 mg/L I in the P 178.287 region, overlaid with scans of a canine control serum and serum obtained from animal 3b 227 min after dosing with 300 mg I/kg and containing 100 mg/L I. The 178.276 nm position at which I was determined with the spectrum shifter off-set software is indicated and the P interference at that point may be visualized. Nonspecific background was also determined at the position indicated in Fig. 1 and used to correct the value at 178.276 before correction for P.



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  		Figure 1. Wavelength scans in the P 178.287 nm channel of the fixed polychromator obtained by incremental positioning of the entrance slit with spectrum shifter software.

Samples analyzed were: 10 mg/L P—··—·; 10 mg/L I ... ... ; canine control serum - - - - - -; serum obtained from animal #3b 227 min after dosing with 300 mg I/kg and containing 100 mg/L I . The baseline was corrected for background noise extrapolated from the position indicated by the arrow.

Correction of P interference.
To routinely correct for the interference, P must be determined at a wavelength free of I and other interferences. The P 214.914 line on the sequential spectrometer portion of the instrument was chosen because it is free of known interferences, and has adequate sensitivity to measure the serum P with high precision for the interelement correction. Day-to-day minor variation in the interelement correction of P on I was accounted for by analysis of P at 50 and 100 mg/L immediately before the start of the sample analysis. Table 3 illustrates the short-term variability seen during typical acquisition of data, a single data point being the average of three replicate 5-s and 2-s integrations for I and P, respectively. Data before and after correction for the P interference are shown. The CV of P at 214.914 was typically 1–3%, whereas the P interference at the wavelength of I on the polychromator varied much less, typically <1%. The uncorrected value obtained at the wavelength of I was also very stable, with CVs typically <1%. However, after the correction for P interference, the CV increased and depended on the concentration of I. At low serum I, 15 and 30 mg/L, the CVs of the corrected values were 11.2% and 3.6%, respectively, in the example given in Table 3 . However, at I >60 mg/L in serum, CVs were <2%. The data suggest a practical lower limit of quantification of 15 mg/L serum I.


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  		Table 3. Typical short-term variability of I and P measurements including I after correction of the interference of P on I.

A sequential ICP-AES method was reported for measurement of serum and urinary I to determine intestinal absorption of iohexol after oral administration (25). No information was provided regarding the accuracy or precision of the method, but the authors used an I wavelength of 178.218 nm. This I line does not appear in conventional wavelength tables (26). It may be assumed that the authors were referring to 178.281 nm, which would be the wavelength intermediate between the P line at 178.287 and I at 178.276, and the position found by a sequential spectrometer with a peak centroid algorithm. If this were the case it would provide no ability for correction of the substantial P interference on the I 178.276 nm line, and would seriously compromise data obtained by a sequential ICP-AES. As the ratio of I to P increases with increased serum or urinary I, the peak centroid would shift toward the lower, I, line and impose a constantly changing P correction on the line. It is not clear from the tabular data presented in the report (25) whether the sizable basal values, reported as 15 to 180 mg I/L but presumably due to P, were subtracted from the subsequent plasma or urine values. The data obtained in the current study indicate that caution should be exercised in the use of sequential ICP-AES to measure I in the presence of substantial P, as would be present in serum or urine.

recovery
Recoveries of I added to serum in 13 experiments over 11 months were >90% (Table 4 ). Recoveries of >=30 mg/L I by the current method (96–100%) were greater and less variable than reported HPLC recoveries (92–106%) in the same concentration range (3). Recoveries were not given for the capillary electrophoresis method at low diagnostic I, but were 97–99% at 200 mg/L (acetonitrile method) and more variable, 95–105%, at 4000 mg/L (dilution method).


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  		Table 4. Accuracy and precision of iohexol determination in supplemented serum samples.

At serum I >=60 mg/L, interassay CVs for the current ICP-AES method were 1.2–3.6%. The precision of the method compares well with other methods in use. Interassay CVs of 2.2–3.5% were reported for HPLC (6)(17)(18)(19), and the capillary electrophoresis method was even less precise, with interassay CVs of 4.7–6.7% (20). Between-run CVs for the colorimetric procedure (16) were excellent, 1.4–2.7% in the range 15–130 mg/L I. However, the colorimetric assay became nonlinear above 130 mg/L, a distinct disadvantage when testing subjects of unknown renal function. For XRF, interassay CVs of 3.6% and 1.4% were reported at 140 mg I/L and 1145 mg I/L, respectively (9).

The assay was linear from 15 to 600 mg I/L on the basis of studies with added iohexol (Materials and Methods). The calculated regression line was y = -0.936 + 0.9979x, with r2 = 0.9995. The equations for the upper and lower 95% confidence intervals were y = 0.3217 + 0.9951x + 6.793e-6x2 and y = -2.194 + 1.001x - 6.793e-6x2 respectively and enclose the line y = x. The ability to accurately measure I down to 15 mg/L effectively extends the "window" of time available to obtain samples in clinical situations where kidney function is unknown at the time of sampling and allows the use of a single (300 mg/kg) dosing regimen for all subjects. In contrast, the newer-model XRF instruments are reported to provide a lower level of quantification of 40 mg/L I in serum (11)(13). However, data obtained at this concentration may have led to compromised results (13). Studies with dogs and cats involving the XRF instrument indicated dosages of 300 mg I/kg would be sufficient to attain serum I >40 mg/L at the later time points for azotemic animals, but nonazotemic dogs and cats may require higher dosages (400 and 600 mg/kg, respectively) (9).

measurement of iohexol in treated animals
Dog 1 (Table 2Up ) was dosed with iohexol at 600 mg I/kg and sampled at 4 and 6 h. I concentrations at 240 and 360 min were 382 and 136 mg/L respectively, which were well above the level of quantification for the method, and indicated that future iohexol doses could be decreased to 300 mg I/kg for estimation of GFR. A more extensive pharmacokinetic experiment was then conducted to characterize the times of the rapid (distribution) phase and slow (elimination) phase of the two-compartment open model. A healthy dog (dog 2) was dosed with 300 mg/kg I and sampled at 5, 19, 61, 178, 235, and 355 min. Pharmacokinetic parameters determined by the two-compartment open model were: A, 1321 mg/L I; B, 982.3 mg/L I; {alpha}, 0.03103 min-1; ß, 0.01161 min-1; t1/2{alpha}, 22.3 min; t1/2ß, 59.7 min; clearance, 2.36 mL min-1 kg-1. The values obtained for t1/2{alpha} and t1/2ß, 22 min and 60 min respectively, were comparable with those previously determined with [125I]iohexol in three dogs as t1/2{alpha} = 14 ± 4 min and t1/2ß = 74 ± 7 min (27). The GFR-2c, 2.36 mL min-1 kg-1, was in the expected range of GFRs reported by Moe and Heiene (7) for nine healthy dogs with the two-compartment model for iohexol clearance (1.6–3.0 mL min-1 kg-1) and [99mTc]DTPA (1.9–3.5 mL min-1 kg-1).

Figure 2 shows the monoexponential elimination curves from four dogs and one cat dosed with 300 mg/kg iohexol and sampled at three time periods during the elimination phase to allow calculation of GFR by the one-compartment model. One azotemic cat with chronic renal failure showed an expected flat elimination curve, with calculated GFR-1c of 0.99 mL min-1 kg-1 (animal 4, Tables 2Up and 5 ). One azotemic dog with acute renal failure due to leishmaniasis also showed an impaired pretreatment GFR-1c of 1.47 mL min-1 kg-1 (dog 3a, Tables 2Up and 5 ), which was in the range of 0.183 to 2.749 mL min-1 kg-1 found for nine dogs with known renal disease or azotemia (7). After treatment for leishmaniasis, the dog's azotemia resolved and the GFR improved to 3.30 mL min-1 kg-1 (dog 3b, Tables 2Up and 5 ) which, along with dogs 2, and 5, was in the expected range of 1.840 to 3.712 mL min-1 kg-1 for nine healthy dogs determined by iohexol clearance with a one-compartment model (7). The GFRs determined by the one-compartment model (Table 5 ) of animals 2, 3b, and 5 also were within the ranges of those determined by endogenous creatinine clearance (2.02–4.47 mL min-1 kg-1) and inulin clearance (2.37–6.54 mL-1 kg-1) (28). The within-run precision (CV) of the GFR-1c determined by triplicate ICP-AES iohexol clearance on a single animal was 0.5%.



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  		Figure 2. Plasma disppearance of I after intravenous administration of iohexol at a dose of 300 mg I/kg to dog #2 {circ}, dog #3a {diamondsuit}, dog #3b {square}, cat #4 •, and dog #5 {blacktriangleup}.

The resulting t1/2ßs and one-compartment GFRs are shown in Table 5Up , along with the correlation coefficient of the least-squares fit of the regression lines.


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  		Table 5. One-compartment pharmacokinetic parameters determined from single dose administration of 300 mg/kg iohexol and correlation coefficient of least-squares fit of three-point elimination phase.

In reviewing the use of the one-compartment model to estimate GFR, Aurell (29) recommended that at least three points be obtained to define the slope, and that the correlation coefficients be >0.98. Table 5Up contains the correlation coefficients determined by linear regression analysis of the three-point elimination phase curves shown in Fig. 2Up and used to calculate the GFR-1c. Although the final points on the I vs time curve included I of 16.4–28.2 mg/L, all r values were >0.99, indicating that the ICP-AES method provided the necessary linearity and precision required for clinical determinations.

In conclusion, the ICP-AES method provides the accuracy and precision necessary to determine serum I at a level of quantification of 15 mg/L. The GFRs and t1/2ßs found with the use of this method for animals with normal renal function were within expected ranges and those for animals with renal insufficiency reflected the clinical condition of the animal. We believe that the method will prove useful for clinical determinations of GFR, especially for infants and small animals.


   Acknowledgments
 
The authors are grateful to Nycomed, Inc., New York, NY, who kindly provided the iohexol used in these experiments. Partial support for the work was provided by the Michigan State University Animal Health Diagnostic Laboratory. We also thank C. Gartrell, R. Green, and R. Reid for their assistance with the clinical management of animals evaluated in this study.


   Footnotes
 
1 Nonstandard abbreviations: GFR, glomerular filtration rate; XRF, x-ray fluorescence; ICP-AES, inductively coupled plasma–atomic emission spectroscopy; TCA, trichloroacetic acid; and PPTS, protein precipitation solution.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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