Pyrimidine and triazine 3-oxide sulfates: a new family of vasodilators

McCall, John M.; Aiken, James W.; Chidester, C. G.; DuCharme, Donald W.; Wendling, Michael G.

doi:10.1021/jm00366a030

Cited by 69 publications

(25 citation statements)

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“…Minoxidil sulfate was also prepared by this method, and the product was separated by precipitation with water (McCall et al, 1983).…”

Section: Protein Covalent Binding (Human Mpo Incubation) [ 14 C]lamomentioning

confidence: 99%

Possible Bioactivation Pathways of Lamotrigine

Lu¹,

Uetrecht²

2007

Drug Metab Dispos

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ABSTRACT:The anticonvulsant lamotrigine is associated with idiosyncratic drug reactions, especially skin rashes. Most idiosyncratic reactions are believed to be caused by reactive metabolites. Previous studies have found evidence that an arene oxide is formed in rats; however, when we incubated radiolabeled lamotrigine with rat liver microsomes virtually no covalent binding was detected, and the expected downstream phenolic metabolites are not observed in humans. Rare cases of agranulocytosis have been associated with lamotrigine therapy, and we found that lamotrigine is oxidized to two different N-chloro products by HOCl. The more reactive Nchloro metabolite forms an adduct with N-acetylhistidine, and covalent binding was observed when radiolabeled lamotrigine was incubated with myeloperoxidase/H 2 O 2 /Cl ؊ . Another lamotrigine metabolite is an N-oxide. If this N-oxide were sulfated, it might be sufficiently reactive to bind to protein. The synthetic N-sulfate reacted with N-acetylserine; however, no covalent binding was detected when the radiolabeled N-oxide was incubated with sulfotransferase. We also investigated the possibility that lamotrigine might be oxidized to a free radical by other peroxidases or oxidized by other enzymes such as prostaglandin H synthase or tyrosinase, but no evidence of oxidation was found, and lamotrigine did not cause any detectable increase in lipid peroxidation in vivo. In view of the virtual lack of covalent binding to hepatic microsomes and the lack of any other likely pathway leading to metabolic activation in the skin, it is possible that the parent drug rather than a reactive metabolite causes lamotrigine-induced skin rashes.

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“…Minoxidil sulfate was also prepared by this method, and the product was separated by precipitation with water (McCall et al, 1983).…”

Section: Protein Covalent Binding (Human Mpo Incubation) [ 14 C]lamomentioning

confidence: 99%

Possible Bioactivation Pathways of Lamotrigine

Lu¹,

Uetrecht²

2007

Drug Metab Dispos

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“…At least 95% of orally administered minoxidil is absorbed from the gastrointestinal tract and is metabolized to the direct-acting vasodilator minoxidil-N-O-sulfate 4 and the less pharmacologically active minoxidil-O-glucuronide (Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

“…hypotensive effect than minoxidil 4 and may also be sequestrated in smooth muscles, perhaps leading to the effect. It appears likely that the prolonged hypotensive effect in this patient was related to a delay in elimination of the active metabolite due to acute renal failure.…”

Section: Discussionmentioning

confidence: 99%

Prolonged hypotension induced by ingesting a topical minoxidil solution: analysis of minoxidil and its metabolites

Kikuchi

Fujita

Onodera

et al. 2016

Acute Medicine & Surgery

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Case: A 47-year-old man ingested 60 mL of a topical solution (3,000 mg minoxidil) and presented with prolonged hypotension.Treatment with dopamine hydrochloride and noradrenaline provided blood pressure control. Serum unchanged minoxidil concentrations at 4 and 16 h after ingestion were 4,994 and 33.9 ng/mL, respectively. Urine concentrations of unchanged minoxidil, minoxidil-O-glucuronide, and minoxidil-N-O-sulfate at 16 h after ingestion were 360.4, 1,953, and 104.5 ng/mL, respectively.Outcome: The serum unchanged minoxidil concentration rapidly decreased over a short interval. However, the patient needed to receive vasopressor support for the first 4 days after being admitted to the hospital. The urine minoxidil-O-glucuronide concentration was higher than the concentrations of unchanged minoxidil and minoxidil-N-O-sulfate. Conclusion:Although the serum concentration of unchanged minoxidil rapidly decreased, ingesting large amounts of a topical minoxidil solution can have serious and prolonged cardiovascular effects. Analyzing the minoxidil-O-glucuronide concentration in urine is useful for diagnosing minoxidil poisoning.

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“…Modulation of the sympathetic nervous system by surgical or chemical sympathectomy or by adaptation of the sympathetic nervous system to the effects of MNX by gradually increasing the dose of MNX did not have a significant impact on the incidence of these lesions (29). The (22), and other ATP-sensitive potassium channel openers in vitro and in vivo (8,14,25,35,38,39). Although the hypotensive effects of cromakalim and pinacidil have been successfully blocked by glibenclamide in vivo (8,34,35) (Fig.…”

Section: Introductionmentioning

confidence: 96%