Renal responses and pharmacokinetics of piretanide in humans: effect of route of administration, state of hydration and probenecid pretreatment.
The influence of route of administration, state of hydration and transport inhibitor probenecid on the renal responses of a loop diuretic, piretanide, were investigated in 14 healthy volunteers. Maximally achieved plasma concentrations after i.v. and oral piretanide were higher in the nonhydrated state [+54% (i.v.); + 68% (oral)], accompanied by significant decreases in mean residence time, renal clearance and fraction of unchanged drug excreted with nonsignificant decreases in t1/2, steady-state volume of distribution and total clearance when compared with the hydrated state. Relative differences between the two hydrated states in maximal plasma concentrations of piretanide remained after probenecid [+26% (i.v.); +55% (oral)] but changes in kinetic parameters did not. Pretreatment with probenecid produced significant increases in absolute peak and plasma diuretic concentrations, t1/2 and mean residence time while decreasing steady-state volume of distribution, total clearance, renal clearance and fraction of unchanged drug excreted without affecting the bioavailability of piretanide. Urinary drug recovery was greater after i.v. than after oral piretanide, the recovery being consistently lower in nonhydrated state [iv: 2.78 (nonhydrated) versus 3.41 mg/24 h (hydrated); oral: 1.93 (nonhydrated) versus 2.76 mg/24 h (hydrated)]. Probenecid pretreatment reduced the overall urinary recovery of piretanide without altering the i.v./oral differences. Excretion of sodium paralleled piretanide excretion throughout the study except after i.v. dosing in the nonhydrated state where changes in drug excretion after probenecid (2.55 versus 1.63 mg/6 h) failed to influence sodium output (167 versus 152 mmol/6 h). These results demonstrate the importance of route of administration and state of hydration in determining the pharmacocological response of loop diuretics within the kidney.
Noormohamed
F H
FH
Department of Clinical Pharmacology and Therapeutics, Charing Cross and Westminster Medical School, Westminster Hospital, London, United Kingdom.
McNabb
W R
WR
Dixey
J J
JJ
Lant
A F
AF
D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D004232:Diuretics / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011339:Probenecid / Q000494:pharmacology; D011897:Random Allocation; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D004232:Diuretics; D013449:Sulfonamides; C015451:piretanide; D011339:Probenecid