Impairment of Hepatic Uptake of Rifamycin Antibiotics by Probenecid, and Its Therapeutic Implications

Kenwright, Simon; Levi, A J

doi:10.1016/s0140-6736(73)92799-2

Cited by 54 publications

(15 citation statements)

References 14 publications

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“…These systems are shared by other compounds because rifampin uptake into hepatocytes could be inhibited by BSP (Kenwright and Levi, 1973;Laperche et al, 1979), cyclosporin (Ziegler and Frimmer, 1986), and renin-inhibiting peptides (Bertrams and Ziegler, 1991). Conversely, BSP (Kenwright and Levi, 1974) and bile acid (Anwer et al, 1978) uptake by rat hepatocytes was inhibited by rifamycins.…”

mentioning

confidence: 99%

Human Organic Anion Transporting Polypeptide-C (SLC21A6) Is a Major Determinant of Rifampin-Mediated Pregnane X Receptor Activation

Tirona

Leake

Wolkoff³

et al. 2003

J Pharmacol Exp Ther

291

198

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mentioning

confidence: 99%

Human Organic Anion Transporting Polypeptide-C (SLC21A6) Is a Major Determinant of Rifampin-Mediated Pregnane X Receptor Activation

Tirona

Leake

Wolkoff³

et al. 2003

J Pharmacol Exp Ther

291

198

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“…Venous blood samples were taken just before valaciclovir dosing and then at 15, 30, 45, 60, 75, and 90 min and at 2, 2.5, 3,4,5,6,8,10,12,16, and 24 h after administration. Samples taken up to 3 h after valaciclovir dosing were assayed for valaciclovir.…”

Section: Methodsmentioning

confidence: 99%

“…Valaciclovir and acyclovir, which have anionic and cationic forms in plasma, are secreted by organic anion and cation transporters. Acyclovir CL R is reduced by probenecid (6), which was thought to be due to inhibition of the renal tubular secretion of acyclovir by the anionic pathway.We investigated the effects of probenecid and cimetidine on valaciclovir pharmacokinetics, as these drugs have been reported to inhibit the metabolism of some compounds and the active membrane transport of a number of organic anions and cations (4,6,8,9,12). Additionally, we examined the effects of probenecid and cimetidine on the pharmacokinetics of acyclovir.…”

mentioning

confidence: 99%

“…We investigated the effects of probenecid and cimetidine on valaciclovir pharmacokinetics, as these drugs have been reported to inhibit the metabolism of some compounds and the active membrane transport of a number of organic anions and cations (4,6,8,9,12). Additionally, we examined the effects of probenecid and cimetidine on the pharmacokinetics of acyclovir.…”

mentioning

confidence: 99%

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Multiple Interactions of Cimetidine and Probenecid with Valaciclovir and Its Metabolite Acyclovir

Bony

Tod

Bidault

et al. 2002

Antimicrob Agents Chemother

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The effects of probenecid and cimetidine on the pharmacokinetics of valaciclovir and its metabolite acyclovir have been investigated. Twelve healthy male volunteers participated in this open single-dose study with a four-way-crossover randomized and balanced design. At the first of four administrations, volunteers in four groups received 1 g of valaciclovir alone, valaciclovir with 1 g of probenecid, valaciclovir with 800 mg of cimetidine, or valaciclovir with a combination of probenecid and cimetidine. At three subsequent administrations, drug regimens were alternated among groups so that each group received each regimen. Probenecid and cimetidine increased the mean maximum concentrations in serum (C max ) of valaciclovir by 23 and 53% and the areas under the concentration-time curves (AUC) for valaciclovir by 22 and 73%, respectively; probenecid and cimetidine also increased the mean acyclovir C max by 22 and 8% and its AUC by 48 and 27%, respectively. The combination had a greater effect than either drug alone. Their effects may be due to competitive inhibition of membrane transport of valaciclovir and acyclovir in the liver and kidney. Neither cimetidine nor probenecid affected the absorption of valaciclovir. Both probe drugs reduced the rate of valaciclovir metabolism but not its extent. These pharmacokinetic modifications did not affect the tolerability of valaciclovir.Valaciclovir (Valtrex) is the L-valine ester of acyclovir and is extensively converted to the antiherpetic compound acyclovir by hepatic first-pass metabolism following oral administration. Its bioavailability as valaciclovir is three-to fivefold greater than acyclovir's oral bioavailability (13). The active metabolite acyclovir is excreted 85% unchanged in the urine, with the rate of renal clearance (CL R ) being three times that of the glomerular filtration rate, indicating that renal excretion has a significant tubular-secretion component. Valaciclovir and acyclovir, which have anionic and cationic forms in plasma, are secreted by organic anion and cation transporters. Acyclovir CL R is reduced by probenecid (6), which was thought to be due to inhibition of the renal tubular secretion of acyclovir by the anionic pathway.We investigated the effects of probenecid and cimetidine on valaciclovir pharmacokinetics, as these drugs have been reported to inhibit the metabolism of some compounds and the active membrane transport of a number of organic anions and cations (4,6,8,9,12). Additionally, we examined the effects of probenecid and cimetidine on the pharmacokinetics of acyclovir. The drug interactions at the renal level were modeled as a function of the concentrations of the interaction drugs in plasma in order to characterize more precisely their mechanisms and potential consequences. MATERIALS AND METHODS Study design.We employed an open, randomized, balanced, crossover study design with four drug treatments separated by intervals of at least 1 week. Twelve healthy male volunteers (age range, 22 to 43 years; weight range, 54 to 111 kg) par...

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“…This effect is most important in the renal tubule, where the secretion of many drugs, metabolites and endogenous compounds is inhibited (Weiner et al, 1964). Probenecid has also been shown in animals to inhibit the biliary elimination of a number of drugs, including indomethacin (Duggan et al, 1977), methotrexate (Kates & Tozer, 1976), rifamycin antibiotics (Kenwright & Levi, 1973) and to decrease the non-renal clearance in man of some biliary excreted drugs (Baber et al, 1978;Stoeckel et al, 1988). In the rat, probenecid itself is secreted into bile by a dose-dependent and saturable process, subject to inhibition by, for example, phenolphthalein (Guarino & Schanker, 1968).…”

Section: Introductionmentioning

confidence: 99%

No effect of probenecid on the renal and biliary clearances of digoxin in man.

Hedman

Angelin

Arvidsson

et al. 1991

Brit J Clinical Pharma

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1. The cardiac glycoside digoxin is subject to a number of pharmacokinetic interactions. This study concerns the influence of the anionic transport inhibitor probenecid on the steady‐state kinetics of digoxin. 2. Six healthy young men were enrolled in the study. After an administration period of 6 days with digoxin only (0.5 to 1 mg p.o. day‐ 1) or digoxin in combination with probenecid (2 g p.o. day‐1; 8 days), digoxin was administered intravenously (0.7 oral dose) on day 7. Plasma and urine samples were taken over 48 h. The biliary clearance of digoxin was measured during day 8 by a duodenal perfusion technique. 3. Probenecid did not affect the plasma clearance (mean +/‐ s.d.: 255 +/‐ 80 vs 266 +/‐ 40 ml min‐1), renal clearance (166 +/‐ 17 vs 155 +/‐ 10 ml min‐1), biliary clearance (106 +/‐ 40 vs 111 +/‐ 50 ml min‐1), elimination half‐life (34.4 vs 35.2 h) or volume of distribution (538 +/‐ 241 vs 566 +/‐ 60 l) of digoxin. 4. Our results suggest that different systems exist in man for the renal and biliary secretion of probenecid and digoxin.

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Impairment of Hepatic Uptake of Rifamycin Antibiotics by Probenecid, and Its Therapeutic Implications

Cited by 54 publications

References 14 publications

Human Organic Anion Transporting Polypeptide-C (SLC21A6) Is a Major Determinant of Rifampin-Mediated Pregnane X Receptor Activation

Human Organic Anion Transporting Polypeptide-C (SLC21A6) Is a Major Determinant of Rifampin-Mediated Pregnane X Receptor Activation

Multiple Interactions of Cimetidine and Probenecid with Valaciclovir and Its Metabolite Acyclovir

No effect of probenecid on the renal and biliary clearances of digoxin in man.

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