Preparation of phenylephrine 3-O-sulfate as the major in vivo metabolite of phenylephrine to facilitate its pharmacokinetic and metabolism studies.

INTRODUCTION: The in vivo disposition and metabolism of phenylephrine have not been establishedby previous analytical methods and there is a lack of available standards for quantitating the metabolites. METHODS: We pursued and compared the preparation of sulfation metabolites of phenylephrine and its ethyl analog etilefrine via chemical and bio-synthesis. RESULTS: Both sulfates were obtained in higher yield and purity through chemical syntheses compared to biosynthesis. DISCUSSION: A facile method for the production of phenylephrine 3-O-sulfate and etilefrine 3-O-sulfate was established. These compounds will be useful in the development of analytical assays for studying the pharmacokinetics of phenylephrine and its main route of metabolism in the presence of formulation changes and pharmacogenetic variation.

Synthesis, characterization, and reactivity of ferrous and ferric oxo/peroxo pivalate complexes in relation to Gif-type oxygenation of substrates.

This study examines structural features and aspects of reactivity of Gif-type reagents, which depend on O2/Zn to mediate oxidation of hydrocarbons. The reagents investigated derive from the use of iron complexes with the anion of the weak carboxylic acid Me3CCO2H (pivalic acid (PivH)) in pyridine/PivH. In these solutions, the known compound [Fe3O(O2CCMe3)6(py)3] is reduced by Zn to generate yellow-green [FeII(O2CCMe3)2(py)4], which readily reverts to [Fe3O(O2CCMe3)6(py)3], and eventually to [Fe3O(O2CCMe3)6(py)3]+, upon exposure to dioxygen. All three species are equally well suited to mediate Gif-like oxygenation of substrates supported by O2/Zn. [FeIII3O(O2CCMe3)6(L)3]+ (L = H2O, py) is converted by H2O2 to afford the hexairon(III) peroxo compounds [Fe6(O2)(O)2(O2CCMe3)12(L)2] (L = Me3CCO2H, py), which feature a [Fe6(eta 2-mu 4-O2)(mu 3-O)2] core previously documented in the closely related [Fe6(O2)(O)2(O2CPh)12(H2O)2]. A similar peroxo species, [Fe6(O2)(O)2(O2CCMe3)2(O2CCF3)10(H2O)2], is obtained upon replacing all pivalate ligands by trifluoroacetate groups with the exception of those pivalates that bridge between the two [Fe3O(O2CCF3)5(H2O)]2+ units. The structure of the [Fe6(O2)(O)2] core in these peroxo species is found to range from a recliner to a butterfly-type conformation. Reduction of [Fe6(O2)(O)2(O2CCMe3)12(HO2CCMe3)2] with NaBH4 generates [Na2Fe4(O)2(O2CCMe3)10(L)(L')] (L = CH3CN, L' = Me2CO; L = L' = Me3CCO2H), which feature a [Na2Fe4(O)2] core possessing a bent butterfly conformation of the [Fe4(O)2] unit. Oxidation of the same peroxo complex by CeIV or NOBF4 regenerates the oxo-bridged [Fe3O(O2CCMe3)6(solv)3]+ (solv = EtOH, H2O, thf). Employment of the sterically encumbered 2-Me-5-Etpyridine provides the tetrairon compound [Fe4(O)2(O2CCMe3)8(2-Me-5-Etpy)2], which can be readily transformed upon treatment with H2O2 to the asymmetric peroxo complex [Fe6(O2)(O)2(O2CCMe3)12(2-Me-5-Etpy)2]. The peroxo-containing complexes oxidize both cis-stilbene and adamantane in either benzene or py/PivH, but only under forceful conditions and at very low yields. The low reactivity and high selectivity (tert/sec = 8) obtained in the oxidation of adamantane suggests that the present type of peroxo species is not directly involved in catalytic Gif-type oxygenations of adamantane.

Formation of a direct mutagen, diazo-N-nitrosoetilefrin, by interaction of etilefrin with nitrite.

Reaction of an antihypotensive drug, etilefrin [alpha-[(ethylamino)methyl]-m-hydroxybenzyl alcohol], with nitrite under mildly acidic conditions produced N-nitrosoetilefrin [alpha-[(N-nitrosoethylamino)methyl]-m-hydroxybenzyl alcohol] (a mixture of syn and anti forms) (Iab) and diazo-N-nitrosoetilefrin [1-(4-diazo-3-oxo-1,5-cyclohexadienyl-2-(N-nitrosoethylamino )ethanol] (a mixture of syn and anti forms) (IIab). Treatment of etilefrin with an equivalent amount of nitrite at pH 3 and 37 degrees C for 4 h gave Iab (yield, 30%) and IIab (yield, 5%). Treatment of etilefrin with 4 eq of nitrite under the same conditions gave Iab (23%) and IIab (53%). Compounds Iab and IIab were each composed of two isomers due to the configuration of the N-nitroso group. While compound Iab was not mutagenic, compound IIab showed mutagenicity to Salmonella typhimurium TA98 and TA100 strains without metabolic activation. Specific mutagenic activity of IIab was 300 his+ revertant colonies for both TA98 and TA100 strains with a dose of 0.1 mumol. Addition of a microsomal activation system little affected the activity. It is noteworthy that this orally administered drug can produce a direct-acting mutagen by reaction with nitrite, which is present in the digestive tract.

[Asymmetrical synthesis of (R)(-) and (S)(+)-etilefrine by enantioselective hydrogenation and the effects of enantiomers in an animal experiment]. / Asymmetrische Synthese des (R)(-)- und (S)(+)-Etilefrins durch enantioselektive Hydrierung und die Wirkungen der Enantiomere im Tierexperiment.

The enantiomers of etilefrine (Effortil) were produced by enantioselective hydrogenation. The optical purity was determined by conversion with (+)-[(R)-tetrahydrofurfuryl-(1S)-camphor-10-sulfonate] to N-[(R)-tetrahydrofurfuryl]-etilefrine and subsequent separation of the diastereomers by HPLC. An animal experiment showed that the (R)(-)-enantiomer is more effective.

Prodrugs of etilefrine: synthesis and evaluation of 3'-(O-acyl) derivatives.

A series of 3'-(O-acyl) derivatives of etilefrine (alpha-[(ethylamino)methyl]-3'-hydroxybenzyl alcohol) was synthesized. Correlations between structure and solubility, pKa value, lipophilicity, and esterase-catalyzed hydrolysis were demonstrated. Of special interest is the 3'-(O-pivaloyl) derivative, which shows, in addition to favorable solubility and improved lipophilicity, marked stability against enzymatic cleavage in blood along with a high rate of hydrolysis in the liver.