N-O-Glucuronides

Minoxidil is absorbed from the Gl tract and is metabolized to its active sulfate metabolite. Plasma concentrations for minoxidil sulfate peak within 1 hour and then decline rapidly. Following an oral dose of minoxidil, its hypotensive effect begins in 30 minutes, is maximal in 2 to 8 hours, and persists for approximately 2 to 5 days. The delayed onset of the hypotensive effect for minoxidil is attributed to its metabolism to its active metabolite. The drug is not bound to plasma proteins. The major metabolite for minoxidil is its N-O-glucuronide, which unlike the sulfate metabolite is inactive as a hypotensive agent. Approximately 10 to 20% of an oral dose of minoxidil is metabolized to its active metabolite, minoxidil O-sulfate, and approximately 20% of minoxidil is excreted unchanged. 

Figure 18.2 Representative receiver operator curves to demonstrate the leave n out validation of K-PLS classification models (metabolite formed or not formed) derived with approximately 300 molecules and over 60 descriptors. The diagonal line represents random. The horizontal axis represents the percentage of false positives and the vertical axis the percentage of false negatives in each case. a. Al-dealkylation. b. O-dealkylation. c. Aromatic hydroxylation. d. Aliphatic hydroxylation. e. O-glucuronidation. f. O-sulfation. Data generated in collaboration with Dr. Mark Embrechts (Rensselaer Polytechnic Institute).

MDMA is effective in 20-30 min from intake and shows a peak plasma level after about 120 min with continued effects for up to 4-6 h plasma half-life is 6-7 h. Metabolism proceeds by two routes. The principal one involves O-demethylation to 3,4-dihydroxymetamphetamine (HHMA) followed by O-methylation to 4-hydroxy-3-metoxymetamphetamine (HMMA) and 3,4-dihydroxyamphetamine (HHA) and subsequent O-glucuronide and sulfate conjugation. The second pathway involves an N-demethylation to MDA, followed by deamination and oxidation to the corresponding benzoic acid derivative, substantially conjugated with glycine. The MDA is a metabolite of both MDMA and MDEA [19]. 

Takenaga, N., Ishii, M., and Kamei, T., Structure-activity relationship in O-glucuronidation of indolocarbazole analogs, Drug Metab. Disposition, 30, 494-497, 2002. 

The metabolism of 6-methylelliptinium (420) in rats (bile and urine) gives rise to the O-sulfate and O-glucuronide conjugates, but no demethylation of the N-6 methyl group (260) (Scheme 68). Likewise, the HRP/H2O2 system gives rise to the ort/io-quinone 421 and the oxazolopyridocarbazole 422, when alanine is present, but not to N-6 demethylation (261). The metabolism of olivacine (4) in rats and microsomes is faster than that of ellipticine, and leads to hydroxylation at the C-7 and C-9 positions (as conjugates) (55). 

Ubels JL, Dennis MH, Mitchell JH, et al. Biological activity of N-(4-hydroxyphenyl) retinamide-O-glucuronide in corneal and conjunctival cells of rabbits and humans. Curr Eye Res 1995 14 1115-1124. 

Haloperidol undergoes extensive metabolism to form a myriad of primary and secondary metabolites (479-486). The principal phase I reactions involve the following oxidative N-dealkylation to initially form 4-fluoro-phenylbenzoylpropionaldehyde (which is rapidly oxidized to the acid) and 4-(4-chlorophenyl)-4-hydroxypiperidine (479,480, 483-485) N-oxidation to form haloperidol-iV-oxide (485) and reversible reduction of the carbonyl group to the alcohol, or reduced haloperidol (481,487). A phase II metabolite, hal-operidol-O-glucuronide, accounts for as much... 

O-glucuronide, diazepam (which is N-demethylated to nordiazepam), and codeine (which is O-demethylated to morphine). 

Second in importance to O-glucuronides are the N-glucuronides formed by reactions... 

Other procarcinogens form the N-hydroxy intermediate that requires transferase-catalyzed conjugation (e.g., O-glucuronide and O-sulfate) to form the ultimate carcinogen." The quantity of ultimate carcinogen" formed should relate directly to the proportion of the dose that binds or alkylates DNA. 

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