Synthesis of 5,6,6-[2H3]finasteride and quantitative determination of finasteride in human plasma at picogram level by an isotope-dilution mass spectrometric method

Abstract

Finasteride is a potent inhibitor of the enzyme steroid 5a-reductase now approved as a drug for the treatment of benign prostatic hyperplasia. We describe an original method for the quantitative determination of finasteride at picogram level in human plasma by isotope-dilution gas chromatography mass spectrometry. 5,6,6-[2H3]Finasteride was synthesized with an high ratio of trideuteration (finasteride/[2H3]finasteride = 0.007) allowing its optimal use as internal standard. Plasma samples were purified in a single-step procedure on solid-phase extraction C~8 columns with a recovery />90%. Samples were injected in the GC-MS instrument without any derivatization and the minimum detection level of finasteride was 50 pg with a signal-to-noise ratio of 6:1. The coefficients of variation for the 5 and 10 ng/ml (plasma) concentrations were 5.8% and 4%, respectively. The method has been applied to the determination of the plasma pharmacokinetic of finasteride in five male volunteers treated with a single 5-mg dose of the drug, affording kinetic parameters which are in good agreement with the values previously reported with a different methodology. The present method results accurate, specific, sensible and reliable for a routinely determination of finasteride at picogram levels.

Highly stereoselective Pictet–Spengler reaction of d-tryptophan methyl ester with piperonal: convenient syntheses of Cialis (Tadalafil), 12a-epi-Cialis, and their deuterated analogues

“…Two deuterated compounds 3 and 4 may be useful for measuring the plasma concentration of these drugs using GC-MS techniques. [29][30][31][32] Percentages of deuterium-labeling in 3 and 4 obtained from the above procedure were higher than 83% at the C-12a position and 90% at the C-3 position. Unfortunately when we tried to purify 3 and 4 by recrystallization in some solvents, almost no change in the purity was obtained at all.…”

A New Look at the 5?-Reductase Inhibitor Finasteride

“…In humans, pharmacokinetic data for 5á-reductase inhibitors are limited and generally reflect the results following a bolus administration of the drug (66 (62,65,100,132). When the pharmacokinetics of finasteride was examined after single and multiple administration of the drug over an increasing dose range (5-100 mg), the relationship between peak plasma concentration and dose of finasteride was linear (100).…”

A rapid, simple, specific liquid chromatographic–electrospray mass spectrometry method for the determination of finasteride in human plasma and its application to pharmacokinetic study

“…These methods include high-performance liquid chromatography (HPLC) [11][12][13][14], polarography [15], liquid chromatography-tandem mass spectrometry [16][17][18] and an isotop dilution mass-spectrometric method [19]. Macek has reviewed about these published papers [20].…”