Pharmacokinetics and the effect of probenecid on the renal excretion mechanism of diprophylline

Masayuki Nadai, Ruttikorn Apichartpichean, Takaaki Hasegawa, Toshitaka Nabeshima

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Abstract

The mechanism of renal excretion of diprophylline (DPP) and the effect of probenecid on the active transport of DPP in renal tubules were investigated in rats. The concentration of DPP in plasma increased in proportion to the doses of 10, 30, and 60 mg/kg. The pharmacokinetic parameters and the urinary excretion of DPP did not change significantly with the dose. These findings indicate that DPP possesses dose‐independent pharmacokinetics. Pharmacokinetic parameters for tubular secretion of DPP, as determined by a single‐injection renal clearance method, were 21.25 μg/mL for the Michaelis‐Menten constant and 102.38 μg/min for maximum velocity. Coadministration of probenecid decreased the total body clearance of DPP but did not change in the steady‐state volume of distribution of DPP. The effect of probenecid concentration on the steady‐state renal clearance of DPP was evaluated by continuously infusing probenecid at various rates. The renal clearance of DPP decreased as the probenecid concentration increased, a result indicating that probenecid inhibits the tubular secretion of DPP. However, probenecid did not inhibit the renal secretion of DPP completely, probably because of the existence of probenecid‐insensitive transport systems for DPP in the renal proximal tubule. The Michaelis‐Menten constant, maximum velocity, and glomerular filtration rate, as calculated with the competitive inhibition model for renal clearance of DPP, correlated well with estimated values after a single intravenous administration, as described earlier. The competitive inhibition constant of probenecid was 15.86 μg/mL.

Original languageEnglish
Pages (from-to)1024-1027
Number of pages4
JournalJournal of Pharmaceutical Sciences
Volume81
Issue number10
DOIs
Publication statusPublished - 01-01-1992
Externally publishedYes

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Dyphylline
Probenecid
Pharmacokinetics
Kidney
Renal Elimination
Proximal Kidney Tubule

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

Nadai, Masayuki ; Apichartpichean, Ruttikorn ; Hasegawa, Takaaki ; Nabeshima, Toshitaka. / Pharmacokinetics and the effect of probenecid on the renal excretion mechanism of diprophylline. In: Journal of Pharmaceutical Sciences. 1992 ; Vol. 81, No. 10. pp. 1024-1027.
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Pharmacokinetics and the effect of probenecid on the renal excretion mechanism of diprophylline. / Nadai, Masayuki; Apichartpichean, Ruttikorn; Hasegawa, Takaaki; Nabeshima, Toshitaka.

In: Journal of Pharmaceutical Sciences, Vol. 81, No. 10, 01.01.1992, p. 1024-1027.

Research output: Contribution to journalArticle

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T1 - Pharmacokinetics and the effect of probenecid on the renal excretion mechanism of diprophylline

AU - Nadai, Masayuki

AU - Apichartpichean, Ruttikorn

AU - Hasegawa, Takaaki

AU - Nabeshima, Toshitaka

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N2 - The mechanism of renal excretion of diprophylline (DPP) and the effect of probenecid on the active transport of DPP in renal tubules were investigated in rats. The concentration of DPP in plasma increased in proportion to the doses of 10, 30, and 60 mg/kg. The pharmacokinetic parameters and the urinary excretion of DPP did not change significantly with the dose. These findings indicate that DPP possesses dose‐independent pharmacokinetics. Pharmacokinetic parameters for tubular secretion of DPP, as determined by a single‐injection renal clearance method, were 21.25 μg/mL for the Michaelis‐Menten constant and 102.38 μg/min for maximum velocity. Coadministration of probenecid decreased the total body clearance of DPP but did not change in the steady‐state volume of distribution of DPP. The effect of probenecid concentration on the steady‐state renal clearance of DPP was evaluated by continuously infusing probenecid at various rates. The renal clearance of DPP decreased as the probenecid concentration increased, a result indicating that probenecid inhibits the tubular secretion of DPP. However, probenecid did not inhibit the renal secretion of DPP completely, probably because of the existence of probenecid‐insensitive transport systems for DPP in the renal proximal tubule. The Michaelis‐Menten constant, maximum velocity, and glomerular filtration rate, as calculated with the competitive inhibition model for renal clearance of DPP, correlated well with estimated values after a single intravenous administration, as described earlier. The competitive inhibition constant of probenecid was 15.86 μg/mL.

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