Minoxidil, conjugates

Dihydralazine and minoxidil (via its sulfate-conjugated metabolite) dilate arterioles and are used in antihypertensive therapy. They are, however, unsuitable for monotherapy because of compensatory circulatory reflexes. The mechanism of action of dihydralazine is unclear. Minoxidil probably activates K channels, leading to hyperpolarization of smooth muscle cells. Particular adverse reactions are lupus erythematosus with dihydralazine and hirsutism with minoxidil—used topically for the treatment of baldness (alopecia androg-enetica). 

Sulfotransferases (SULTs) are important for the metabolism of a number of drugs, neurotransmitters, and hormones, especially the steroid hormones. The cosubstrate for these reactions is 3 -phosphoadenosine 5 -phosphosulfate (PAPS) (Fig. 4.1). Like the aforementioned enzymes, sulfate conjugation typically renders the compound inactive and more water soluble. However, this process can also result in the activation of certain compounds, such as the antihypertensive minoxidil and several of the steroid hormones. Seven SULT isoforms identified in humans, including SULTs lAl to 1A3, possess activity toward phenolic substrates such as dopamine, estradiol, and acetaminophen. SULTIBI possesses activity toward such endogenous substrates as dopamine and triiodothyronine. SULTIEI has substantial activity toward steroid hormones, especially estradiol and dehydroepiandrosterone, and toward the anti-... 

Sulfotransferase activity is not restricted to minoxidil. The ability of other pyrimidine-, as well as pyridine-, triazine- and imidazole N-oxides to serve as substrates was investigated using soluble liver preparation and PAPS. The variety of structures studied indicated that heteroaromatic N-oxides are generally metabolized by sulfotransferases183. Presumably, all of the heterocycles tested were conjugated via their N-oxide oxygens. 

Important drug substrates for the SULT enzymes are acetaminophen, minoxidil, and isoproterenol. The SULT enzymes play an important role in the bioactivation of some chemicals through the conjugation of alcohols to form reactive species. This reaction is most notable in the activation of hydroxylamines derived from arylamines.70,71... 

An intriguing and very rare reaction of conjugation occurs for minoxidil (21)(Fig. 13.19), an hypotensive agent also producing hair grovvth. This drug is an N-oxide, and the actual active form responsible for the different therapeutic effects is the AT,0-sulfate ester (22) (56). 

ABSORPTION, METABOLISM, AND EXCRETION Minoxidil is well absorbed from the GI tract. Although peak concentrations of minoxidil in blood occur 1 hour after oral administration, the maximal hypotensive effect of the dmg occurs later, possibly because formation of the active metabolite is delayed. About 20% of the absorbed drug is excreted unchanged in the urine the main route of elimination is by hepatic metabolism. The major metabolite of minoxidil is the glucuronide conjugate at the /V-oxide position. This metabolite is less active than minoxidil but has a long tj. Minoxidil has a tj in plasma of 3 hours, but its duration of action is 24 hours or longer. 

Sulfonation is generally a detoxification pathway whereby the conjugated product has greater water solubility and is therefore excreted more readily from the body. However, several chemicals have been shown to form mutagenic and carcinogenic reactive electrophiles upon sulfonation (Glatt, 2000). Additionally, it is the sulfonated forms of minoxidil and cholecystokinin that elicit biologic activity (Weinshilboum et al., 1997). 

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