Multiple interactions of cimetidine and probenecid with valaciclovir and its metabolite acyclovir.

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.

Quantitation of 6-(pyridin-3-yl)quinolin-2(1H)-one, a cardiac stimulant, and its N-oxide metabolite in dog plasma by high-performance liquid chromatography.

A method is described for the determination of UK-57,400 (I), a 6-substituted quinoline cardiotonic, and its pyridyl-N-oxide in dog plasma. The analytes are selectively retained from plasma (1 ml) on a solid-phase extraction column and eluted with 1 ml of methanol. After evaporation to dryness, the residue is reconstituted in 100 microliters of the mobile phase. Chromatography is carried out on a Spherisorb 5 microns phenyl high-performance liquid chromatography column, with ultraviolet detection. Calibration curves are linear for concentrations from 10 to 100 ng ml-1. For I, the coefficients of variation at highest and lowest concentrations are 1 and 14%, respectively, while the corresponding figures for the pyridyl-N-oxide metabolite are 4 and 10%, respectively. Sample recovery from extraction is greater than 90%. The limit of detection is 4 ng ml-1 for both analytes.