Disposition of drugs in cystic fibrosis. IV. Mechanisms for enhanced renal clearance of ticarcillin.
To investigate the hypothesis that renal secretion of penicillins is enhanced in cystic fibrosis the maximal tubular secretion rate (Tmax) of ticarcillin and the serum concentration of ticarcillin at half-maximal secretion rate (TC50) were determined in patients with cystic fibrosis (n = 6) and control subjects (n = 6). Each subject received three consecutive constant-rate intravenous infusions of ticarcillin (4, 13, and 70 mg/kg/hr; 2 1/2 hours each) simultaneously with a constant-rate (30 mg/kg/hr) infusion of insulin. Urine samples were collected at 1/2-hour intervals and serum samples at the midpoint of the urine collections. Ticarcillin and inulin concentrations in serum and urine were determined by high-performance liquid chromatographic and a spectrophotometric method, respectively. Ticarcillin serum protein binding was determined by ultrafiltration. Steady-state ticarcillin serum concentrations were achieved at all three infusion rates. The TC50 was significantly lower (p < 0.05) in patients with cystic fibrosis (33.7 +/- 12.2 micrograms/ml) compared with that in control subjects (77.6 +/- 38.4 micrograms/ml). In contrast, the Tmax was similar (cystic fibrosis, 0.25 +/- 0.12 mg/min/kg; control, 0.22 +/- 0.14 mg/min/kg; p > 0.05). These data indicate that renal clearance of penicillins is enhanced in cystic fibrosis because of greater affinity of the renal secretory system for these drugs.
Wang
J P
JP
Department of Pharmaceutics, University of Washington, Seattle 98195.
Unadkat
J D
JD
al-Habet
S M
SM
O'Sullivan
T A
TA
Williams-Warren
J
J
Smith
A L
AL
Ramsey
B
B
D000293:Adolescent; D000328:Adult; D003550:Cystic Fibrosis / Q000378:metabolism*; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007262:Infusions, Intravenous; D007444:Inulin / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D012044:Regression Analysis; D013982:Ticarcillin / Q000008:administration & dosage / Q000493:pharmacokinetics*
D007444:Inulin; D013982:Ticarcillin