Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p-aminohippuric acid and pindolol.
OBJECTIVE
Previous studies suggest that estimated creatinine clearance, the conventional measure of renal function, does not adequately reflect changes in renal drug handling in some patients, including the immunosuppressed. The aim of this study was to develop and validate a cocktail of markers, to be given in a single administration, capable of detecting alterations in the renal elimination pathways of glomerular filtration, tubular secretion and tubular reabsorption.


METHODS
Healthy male subjects (n = 12) received intravenously infused 2500 mg sinistrin (glomerular filtration) and 440 mg p-aminohippuric acid (PAH; anion secretion), and orally administered 100 mg fluconazole (reabsorption) and 15 mg rac-pindolol (cation secretion). The potential interaction between these markers was investigated in a pharmacokinetic study where markers (M) or fluconazole (F) were administered alone or together (M + F). Validated analytical methods were used to measure plasma and urine concentrations in order to quantify the renal handling of each marker. Plasma protein binding of fluconazole was measured by ultrafiltration. All subjects had an estimated creatinine clearance within the normal range. The renal clearance of each marker (mean+/- s.d.) was calculated as the ratio of the amount excreted in urine and the area-under-the-concentration-time curve. Statistical comparisons were made using a paired t-test and 95% confidence intervals were reported.


RESULTS
The renal clearances of sinistrin (M: 119 +/- 31 ml min(-1); M + F: 130 +/- 40 ml min(-1); P = 0.32), PAH (M: 469 +/- 145 ml min(-1); M + F: 467 +/- 146 ml min(-1); P = 0.95), R-pindolol (M: 204 +/- 41 ml min(-1); M + F: 190 +/- 41 ml min(-1); P = 0.39; n = 11), S-pindolol (M: 225 +/- 55 ml min(-1); M + F: 209 +/- 60 ml min(-1); P = 0.27; n = 11) and fluconazole (F: 14.9 +/- 3.8 ml min(-1); M + F: 13.6 +/- 3.4 ml min(-1); P = 0.16) were similar when the markers or fluconazole were administered alone (M or F) or as a cocktail (M + F).


CONCLUSIONS
This study found no interaction between markers and fluconazole in healthy male subjects, suggesting that a single administration of this cocktail of markers of different renal processes can be used to simultaneously investigate pathways of renal drug elimination.
Gross
A S
AS
Department of Clinical Pharmacology, Royal North Shore Hospital, Sydney, Australia.
McLachlan
A J
AJ
Minns
I
I
Beal
J B
JB
Tett
S E
SE
D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000652:urine; D015415:Biomarkers / Q000097:blood* / Q000652:urine*; D003404:Creatinine / Q000097:blood / Q000378:metabolism / Q000652:urine; D004338:Drug Combinations; D016903:Drug Monitoring / Q000706:statistics & numerical data; D015725:Fluconazole / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D005919:Glomerular Filtration Rate; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D009844:Oligosaccharides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D010869:Pindolol / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D017595:Renal Plasma Flow; D013997:Time Factors
D000935:Antifungal Agents; D015415:Biomarkers; D004338:Drug Combinations; D009844:Oligosaccharides; D015725:Fluconazole; D003404:Creatinine; D010869:Pindolol; C064636:sinistrin