Influence of angiotensin II-induced alterations in renal flow on excretion of cefonicid in isolated perfused rat kidneys

Abstract

The effects of variations in renal perfusate flow on the excretion of cefonicid was examined in isolated perfused rat kidneys. Cefonicid, an expanded-spectrum cephalosporin, is primarily eliminated by active tubular secretion and is neither metabolized nor reabsorbed in the isolated kidney. We used angiotensin II (All), a strong vasoconstrictor hormone of the afferent and the efferent arterioles in the kidney, to determine whether the renal and secretion clearances, as well as the excretion ratio (ER = CLR/I[I X GFRJ, where CLR is renal clearance, f. is the unbound fraction, and GFR is glomerular filtration rate), of this low-extraction compound can be altered by a decreased perfusion flow. Control studies were performed in the absence (n = 5) and presence (n = 4) of All; cefonicid studies were performed in the absence (n = 4) and presence (n = 5) ofAII. AII (1 to 4 ng/min) and cefonicid (5 to 10 p.g/min) were infused into the perfusate. Cefonicid was assayed by high-performance liquid chromatography, and its protein binding was determined by ultrafiltration. AII decreased the perfusate flow rate and increased the renal vascular resistance and filtration fraction of the isolated kidney in the presence and absence of cefonicid. The glomerular filtration rate remained unchanged among the groups. The fractional excretion of glucose was low and steady, indicating a well-preserved tubular function. Although the unbound fraction was unchanged between treatments, the renal and secretion clearances and the excretion ratio of cefonicid were reduced by about 40%o in the presence of All (excretion ratios, 10.3 without AII versus 6.03 with All). These results suggest that the altered clearance parameters of cefonicid are the result of a flow-induced change in the intrinsic secretory transport of the drug.A major factor in the ability of an organ to remove a compound from the circulation is the rate at which the compound is delivered to the organ. The effect of flow rate on this drug removal process is critical, especially for those drugs in which the difference between the arterial and venous concentrations across the organ is very high (i.e., drugs with a high extraction ratio). However, the ability of disease to cause blood flow-induced changes in the hepatic clearance of low-extraction drugs has also been established (19,22). Hence, it is relevant to consider whether the relationships between clearance and organ flow that operate for drug elimination from the liver apply as well for renal drug elimination.The utility of the isolated perfused rat kidney in the evaluation of the disposition of compounds has been shown previously (3,21). Isolated organs enable the study of renal function under states in which variables can be carefully and systematically changed (13,14). Cefonicid, an expandedspectrum cephalosporin, is 96% bound in humans (at 100 p,g/mL), is actively secreted, and is neither metabolized nor reabsorbed in the isolated kidney (20a). In addition, cefonicid is a compound of low renal extraction in the isolated ...

Effect of angiotensin II-induced changes in perfusion flow rate on chlorothiazide transport in the isolated perfused rat kidney

“…Pressure changes are an unlikely mechanism for the reduction in chlorothiazide secretion since only a modest increase in pressure is observed in this treatment group (chlorothiazide + AI1). Similar reductions in secretory clearance were also observed for furosemide and cefonicid in rat IPK experiments in which AII caused dramatic hemodynamic changes but pressure was unchanged (5,24).…”

Disposition of quinapril and quinaprilat in the isolated perfused rat kidney

“…There were no significant differences in IPK function when comparing quinapril vs. quinaprilat administration with one exception; GFR differed by about 20% in these studies. Overall, physiologic parameters were within the normal range of values for this technique (23)(24)(25)(26)(27)(28), and were stable for the duration of each experiment.…”

Tubular transport mechanisms of quinapril and quinaprilat in the isolated perfused rat kidney: Effect of organic anions and cations

“…FE~oa~m and urine flow rate were significantly greater when quinaprilat was coperfused with high dose p-aminohippurate (10,000• This finding is similar to that described earlier for quinapril • p-aminohippurate and probably reflects an osmotic diuretic effect. Physiologic parameters were within the normal range of values for this technique (13)(14)(15)(16)(17)(18), and were stable for the duration of each experiment.…”