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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.

The effects of urine flow and pH on methotrexate renal clearance were studied in seven conditioned male Beagle-Mongrel dogs. Steady-state plasma methotrexate and inulin concentrations were achieved by i.v. infusions preceded by i.v. bolus doses. Plasma and urine concentrations of methotrexate were quantitated by a sensitive high-performance liquid chromatographic assay, while those of inulin were measured by a colorimetric method. Since plasma protein binding of methotrexate was pH and concentration independent, methotrexate/inulin renal clearance without correcting for plasma binding was used for most of the data analyses. The results showed that the renal clearance ratios at the plasma methotrexate levels (approximately 0.1, 1.0, 20.0 and 100 micrograms/ml) studied remained relatively constant when urine pH (differences of up to about 2.5 units) and flow rate (differences of up to approximately 30 times) were changed. This indicated that renal reabsorption of methotrexate in these dogs was negligible. However, concentration-dependent renal clearance was observed. The mean renal clearances were 3.84, 3.94, 2.73, and 2.72 ml/min/kg at plasma concentrations of about 0.1, 1.0, 20.0, and 100.0 micrograms/ml, respectively, when urine was alkalized by sodium bicarbonate. The corresponding clearances were 4.02, 4.28, 2.62,and 2.65 ml/min/kg when urine was acidified by ammonium chloride. These showed the existence of saturable tubular secretion of methotrexate. No 7-hydroxy-methotrexate, a metabolite found in other species, was detected in the urine and plasma of the dogs.

Extended release formulations did not prolong absorption of L-735,524 in dogs. Optimal L-735,524 absorption was dependent on solubility in an acidic environment in the duodenum.