Determinants of renal drug elimination: The role of protein binding and organ perfusion on the renal excretion of cefonicid.
dc.contributor.author | Rodriguez Sainz, Carlos A. | en_US |
dc.contributor.advisor | Smith, David E. | en_US |
dc.date.accessioned | 2014-02-24T16:30:13Z | |
dc.date.available | 2014-02-24T16:30:13Z | |
dc.date.issued | 1991 | en_US |
dc.identifier.other | (UMI)AAI9208636 | en_US |
dc.identifier.uri | http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:9208636 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/105773 | |
dc.description.abstract | Cefonicid is mainly eliminated by tubular secretion, a process that has been reported to be dependent on the total drug concentration. Studies with other drugs of low renal extraction, by contrast, have shown that the unbound drug concentration is the driving force for carrier-mediated secretion. To clarify this discrepancy, studies using the isolated perfused rat kidney were performed in 6% bovine serum albumin (BSA) at initial concentrations of 200 $\mu$g/mL and 20 $\mu$g/mL, and in a combination of 4% BSA/2% human serum albumin (HSA) at initial concentrations of 200 $\mu$g/mL. These combinations were chosen based on analyses that showed preferential binding ex vivo of cefonicid to HSA as opposed to BSA. The excretion ratio (ER = $CL\sb{R}$/ (fu x GFR)) of cefonicid decreased with increasing unbound concentrations, whereas no apparent relationship with total concentration was evident. At similar total concentrations of cefonicid, the renal clearance remained unchanged; the secretion clearance was higher for the 4% BSA/2% HSA experiments, reflecting the reduced unbound fraction and unbound drug concentration of cefonicid. The excretion ratio data were compatible with a model in which Michaelis-Menten kinetics were required to describe active transport ($V\sb{\rm max}$ = 16.6 $\pm$ 1.5 $\mu$g/min, $K\sb{m}$ = 1.63 $\pm$ 0.29 $\mu$g/mL, and $CLu\sb{int,s}$ = 10.2 $\pm$ 1.0 mL/min; estimate $\pm$ SE) and secretion was dependent on the unbound cefonicid concentration. The effect of changes in renal perfusate flow via angiotensin II (AII) on the clearance parameters of cefonicid was also examined. Control and cefonicid studies were performed in the absence and presence of AII. AII (1-4 ng/min) and cefonicid (5-10 $\mu$g/min) were infused into the perfusate. AII decreased the perfusate flow rate and increased the renal vascular resistance and the filtration fraction in the presence and in the absence of cefonicid. The glomerular filtration rate remained unchanged among the groups and tubular function was preserved. Although the unbound fraction was unchanged between groups, the renal and secretion clearances, and the excretion ratio were reduced by about 40% in the presence of AII (ER = 10.3 without AII vs. 6.03 with AII). These results suggest that the altered clearance parameters of cefonicid reflect a flow-induced change in the intrinsic secretory transport of the drug. | en_US |
dc.format.extent | 163 p. | en_US |
dc.subject | Health Sciences, Pharmacology | en_US |
dc.subject | Engineering, Biomedical | en_US |
dc.subject | Health Sciences, Pharmacy | en_US |
dc.title | Determinants of renal drug elimination: The role of protein binding and organ perfusion on the renal excretion of cefonicid. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Pharmaceutics | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/105773/1/9208636.pdf | |
dc.description.filedescription | Description of 9208636.pdf : Restricted to UM users only. | en_US |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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