Contrast media and glomerular filtration: dose dependence of clearance for three agents.

Determination of plasma clearance of contrast agents has been advocated as a means to assess glomerular filtration rate. To evaluate the feasibility of different agents for this purpose, we have compared, in healthy volunteers, the dose dependence of plasma clearance for three contrast media (iohexol, a nonionic agent, and iothalamate and metrizoate, which are ionic substances), with special emphasis on the lower dose range (2-20 mL corresponding to 0.9-12.9 g, depending on dose and agent). Iohexol and iothalamate were cleared at constant rates, irrespective of given dose, whereas metrizoate clearance increased significantly at lower doses. In general, the clearances or iothalamate and metrizoate were, respectively, moderately and markedly higher than that of iohexol. The clearance of different doses of metrizoate (2 mL versus a radiographic dose of 40 mL or more) was also compared with the clearance of [51Cr]EDTA in two groups of patients with reduced renal function. When compared with [51Cr]EDTA in patients with renal dysfunction, metrizoate was cleared significantly faster after a 2-mL dose, whereas clearances were identical when the metrizoate dose was 40 mL or more. These findings indicate that tubular secretion plays an active role in the elimination of metrizoate. The pharmacokinetic properties of iohexol, in combination with its low toxicity, make it a suitable agent for determination of glomerular filtration rate in clinical practice.

Penetration of fleroxacin into prostatic secretion and prostatic adenoma tissue.

In 12 elderly patients, plasma, prostatic secretion and adenoma tissue concentrations of fleroxacin were determined 1-4 h following oral administration of 400 mg. The plasma concentrations ranged between 0.4 and 5.5 micrograms/ml (median 3.7 micrograms/ml), the mean tissue concentrations were slightly higher. The concentrations in prostatic secretion were about one third of the simultaneous plasma concentrations. High concentrations of the concomitantly administered ioxithalamic acid in prostatic secretion are considered as indicative of urinary contamination, and in this case the fleroxacin concentrations are questionable. The drug levels in prostatic adenoma tissue were similar to the concomitantly measured plasma levels.

A nonradioactive iothalamate method for measuring glomerular filtration rate and its use to study the renal handling of cibenzoline.

A high-pressure liquid chromatographic method was developed to measure nonradioactive iothalamate in serum and urine for use in estimating glomerular filtration rate (GFR). This method was used to study the renal handling of cibenzoline, an experimental antiarrhythmic drug. The mean cibenzoline clearance was 3.5 +/- 2.5 (SD) times the glomerular filtration rate. The clearance of non-protein-bound cibenzoline was seven times GFR, indicating excretion by the renal tubular secretory pathway for organic bases. This drug, at the doses used, did not lower creatinine clearance, indicating that the effect of basic drugs competing with creatinine for the base secretory pathway appears to be dose and drug dependent.

Renal and non-renal clearances of iothalamate.

An evaluation of the literature indicated that certain aspects of the disposition kinetics of iothalamate, important to the accurate determination of glomerular filtration rate in dogs and humans, remain to be resolved. The simultaneous clearances of iothalamate and inulin in 5 dogs were determined at three steady-state iothalamate plasma levels (2, 10, and 40 micrograms ml-1) following various rates of intravenous infusion. The iothalamate clearances, both renal and non-renal, were concentration-independent. The overall mean non-renal clearance was 18 per cent (ranging from 9 to 25 per cent) of its plasma clearance. The mean iothalamate/inulin renal clearance ratio was about 0.84 with individual values ranging from 0.72 to 0.95. The significant (4-26 per cent) plasma protein binding of iothalamate in these dogs was the main reason for the lower-than-unity clearance ratios obtained. The literature indicates the existence of up to 25 per cent of non-renal elimination in humans with normal renal function; this is comparable to the present results obtained with dogs but contrary to the assumption, sometimes reported in the literature that non-renal elimination is essentially absent in humans. Binding of iothalamate to plasma proteins from humans was not found in the present study. The above results suggest that for accurate glomerular filtration rate determination in humans and dogs, especially for those with renal impairment, renal clearance rather than plasma clearance should be used, and in the case of dogs it should also be corrected for plasma protein binding. Iothalamate in plasma and urine was analysed by a simple, micro high-performance liquid chromatographic method with UV detection.

High-performance liquid chromatography analysis of mezlocillin, piperacillin, their degradation products, and of ioxitalamic acid in plasma and urine of healthy volunteers.

In plasma and urine of 10 healthy volunteers after intravenous administration of 4 g mezlocillin and piperacillin, respectively, the parent compounds as well as degradation products were assayed by high-performance liquid chromatography. Ioxitalamic acid, a renal contrast medium, was administered simultaneously, in order to measure the glomerular filtration rate, and to control the collection of 24-h urine. As metabolite of mezlocillin the corresponding penicilloic acid only was found, whereas in the case of piperacillin a further degradation product was observed. Half of the doses given was recovered in the urine as unchanged drugs, and in addition 5-10% as metabolites. No differences were found in the pharmacokinetic behaviour of both antibiotics.

Simple and micro high-performance liquid chromatographic method for simultaneous determination of p-aminohippuric acid and iothalamate in biological fluids.

A simple, rapid and micro high-performance liquid chromatographic method was developed for separate or simultaneous determination of p-aminohippuric acid and iothalamate in plasma and urine using p-aminobenzoic acid as an internal standard. The method involved deproteinizing samples with two volumes of acetonitrile followed by injection of 5 microliters of deproteinized supernatant onto a C18 reversed-phase column. The mobile phase contained 3.5% acetonitrile in 0.04% phosphoric acid and flowed at a rate of 1.5 ml/min. The column effluent was monitored by an ultraviolet detector at 254 nm. Retention times for p-aminohippuric acid, iothalamate and p-aminobenzoic acid were approximately 4.5, 6 and 8 min, respectively. This method requires as little as 5 microliters of sample and can be used to measure accurately down to 1 microgram/ml p-aminohippuric acid and 0.5 microgram/ml iothalamate in plasma samples. The coefficients of variation of the assay with or without the use of internal standard were generally low (below 7%). No interferences from endogenous substances or any drugs tested were found.

Contrast enhancement pharmacokinetics of six ionic and nonionic contrast media.

The contrast enhancement of six contrast media (CM) was compared in 13 tissues of the rat after rapid intravenous bolus injection. The rats were sacrificed at 0 and 40 seconds and 2, 5, and 15 minutes after contrast injection. 125I labeled diatrizoate, metrizamide, ioxaglate, iohexol, iopamidol, and a nonionic dimer, iodecol, were each injected at a dose of 612 mg iodine per kg body weight, and iodine concentration (IC) and contrast enhancement were calculated from radioactivity measurements. Higher blood IC values were obtained with the nonionic CM; similar enhancement patterns were seen in the spleen, heart, lungs, and brain. Renal IC was directly related to the number of iodine atoms per ion or molecule of CM. In consequence, renal IC was inversely related to the CM osmolality, but no such correlation was seen with the blood IC. Metrizamide produced the greatest IC in the organs of the gastrointestinal tract. There was no apparent correlation of IC with molecular structure of physicochemical parameters of the CM in any of the other tissues studied.

Correlation of I-125 iothalamate and tc-99m DPTA measurements of GFR using the single injection method.

Simultaneous renal imaging and determination of GFR can be obtained using Tc-99m DTPA. In order to assess the accuracy of the GFR value, a comparison was made between commercial sources of Tc-99m DTPA and I-125 iothalamate. The calculation assumed monoexponential loss of each radiopharmaceutical from the renal compartment. Plasma measurements were made at two sampling intervals, 90 to 120 minutes and 180 to 240 minutes. An apparent volume of distribution calculated for plasma concentrations at 2 hours and 3 hours was examined as a single sample indication of GFR. GFR values appear to be higher with DPTA than with iothalamate at the earlier interval. Choice of the later sampling times may be desirable for patients with known renal disease. The apparent volume of distribution at 3 hours may be a convenient single sample for monitoring or surveying patients for renal disease.

Prediction of glomerular filtration rate by serum creatinine and beta 2-microglobulin.

The reciprocal of serum creatinine concentration (1/Cr) is often used to predict glomerular filtration rate (GFR). Serum creatinine also varies with age, size, and muscle mass, and so it may inaccurately estimate GFR. The reciprocal of serum beta 2-microglobulin (1/beta 2mu) has been proposed as an alternative estimator of GFR. This study compares 1/Cr and 1/beta 2mu as predictors of GFR as measured by 125I-iothalamate clearance (CIOT) and creatinine clearance (CCr) in 29 subjects with a wide range of age, size and kidney function, and including 12 chronic hemodialysis patients. 1/beta 2mu was a better predictor of CIOT (r=0.90) and CCr (r=0.87) than 1/Cr (r=0.50 and 0.78) was. In fact, in the nondialysis population, 1/beta 2mu predicted CIOT (r=0.86) about as well as CCr predicted CIOT (r=0.87). Beta 2mu was less dependent on body size than Cr and unlike Cr, was not influenced by dialysis and did increase as GFR decreased with age. Beta 2mu can be useful as an alternative clinical estimate of GFR, particularly when Cr is considerably influenced by factors other than renal function.

Error dependent on renal function when monoexponential equation assumed. Serum clearances of 125I-iothalamate and 131I-o-iodohippurate.

An example from the literature has been used to demonstrate errors involved in calculating drug clearance by inappropriate use of the apparent drug distribution volume Vdext. The Vdext is always an overestimate of the true volume of distribution in a multicompartment system, and the degree of overestimation in using it to calculate clearance for such a system will increase as renal function increases. Drug dosages calculated on the basis of overestimated clearance values may give rise to overdosage in normal individuals, or therapeutic failure in severely uremic patients. Problems associated with the use of an oversimplified pharmacokinetic model for clearance calculations are discussed, together with the concept of model-independent calculations.

Measurement of regional cerebral blood volume by computerized axial tomography.

Computerized tomography has been used for the estimation of regional cerebral blood volume in a group of 18 patients. Sodium iothalamate was injected intravenously (1.75 ml/kg) to increase the absorption of x-rays in the cerebral circulation. A mean value of 5.7 ml/100 g was found for the cortex and 5.1 for tha thalamus.

Apparent volumes of distribution of 125-I-lothalamate and inulin in chickens.

The suitability of utilizing 125-I-iothalamate to estimate the volume of extracellular fluid was assessed in ureterally ligated chickens. Subsequent to intravenous administration the movement of labeled iothalamate from the plasma compartment follows closed two-compartment kinetics and equilibration between vascular and extravascular phases is attained in about 20 minutes. The volume of distribution of 125-I-iothalamate prior to and following the influsion of 0.15 M NaCl (equal to 15% of the estimated ECFV) averaged 23.6 plus or minus 0.61 and 28.4 plus or minus 0.22% of the body weight, respectively. The observed postsaline labeled iothalamate space did not differ statistically from the expected value. When administered simultaneously inulin penetrates into an apparent volume that is 75% of the labeled iothalamate space after 60 minutes. The content of 125-I-iothalamate is relatively high in liver and kidney tissue and suggests that these are major sites where removal of the indicator from plasma occur. It is suggested that 125-I-iothalamate, under appropriate conditions, could be used to measure the plasma volume and the extravascular fluid with which plasma is in rapid diffusion equilibrium.