Sulfated acetaminophen

Sulfate conjugation appears to be fully developed immediately prior to or at the time of birth. Infants and young children readily sulfate acetaminophen in adults the major metabolic route is glucuronidation. Little is known about acetylation in neonates or infants. It is believed that neonates have an extremely low capacity for acetylation at birth, but this pathway matures at approximately 20 days of age. ... 

Figure 40-2. Formation of 5 -phosphoadenosine 3 -phosphosulfate (PAPS) and sulfated acetaminophen.

The duration of action of acetaminophen is limited by the formation of water-soluble derivatives of the phenol (glucuronide and sulfate) that are then excreted via the kidney. Protection i)f the phenol as an ether inhibits such inactivation without diminishing biologic activity. Acetylation of p-ethoxyaniline iffords the widely used peripheral analgesic, phenacetin (25). ... 

Many process mixtures, notably fermentations, require sample preconcentration, microdialysis, microfiltration, or ultrafiltration prior to analysis. A capillary mixer has been used as a sample preparation and enrichment technique in microchromatography of polycyclic aromatic hydrocarbons in water.8 Microdialysis to remove protein has been coupled to reversed phase chromatography to follow the pharmacokinetics of the metabolism of acetaminophen into acetaminophen-4-O-sulfate and acetaminophen-4-O-glucu-ronide.9 On-line ultrafiltration was used in a process monitor for Aspergillus niger fermentation.10... 

In general, phase I reactions, such as oxidation and ra-demethylation are delayed in the neonate but are fully operational at or above adult levels by 4-6 months of age in the full-term neonate [27a-30]. Conjugation pathways, such as glucuronidation, do not approach adult values until 3 or 4 years of age. Sulfation activity does appear to reach adult levels in early infancy. For drugs that are subject to metabolism by both pathways, such as acetaminophen, the efficient activity of the sulfation pathway allows infants and children to compensate for low glucuronidation ability... 

A cell with a small Pt disk working electrode coated with a polyelectrolyte multilayer made of poly(allylamine)-poly(vinyl sulfate), a Pt wire counterelectrode and a reference SCSE may be used for selective amperometric determination of H2O2, in the presence of ascorbic acid (22), uric acid (29) and acetaminophen (148). The latter three compounds show a significant response with the bare working electrode at +0.6 V while a practically nil one with the coated electrode. The reason for this selectivity may be an exclusion effect by the coating. ... 

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-... 

Quercetin has been found to inhibit P-gp-mediated efflux of ritonavir in Caco-2 cells (47), to reduce the oxidation of acetaminophen in rat liver microsomes and HepG2 cells (48), and to inhibit the metabolism of midazolam and quinidine in human liver microsomes (49). It did not have an effect on CYP3A4-mediated metabolism and P-gp-mediated transport of saquinavir (41). Rutin was demonstrated to moderately increase the uptake of idar-ubicin in an isolated perfused rat lung model, and also the outflow recovery of the major metabolite idarubicinol, possibly by affecting P-gp (45). Nobe-litin and tangeretin were shown to inhibit OATP-B-mediated uptake of estrone-3-sulfate into human embryonic kidney cells (23). 

Sulfation Phosphoadenosyl phosphosulfate Sulfotransferase (cytosol) Phenols, alcohols, aromatic amines Estrone, aniline, phenol, 3-hydroxy-coumarin, acetaminophen, methyldopa... 

Williams, D. B., S. A. Varia, V. J. Stella, and I. H. Pitman. 1983. Evaluation of the prodrug potential of the sulfate esters of acetaminophen and 3-hydroxymethyl-phenywinl. Pharm.14 113-120. 

A good example of the importance of tissue availability of the conjugating chemical is found with acetaminophen. At normal therapeutic doses, acetaminophen is safe, but can be hepatotoxic at high doses. The major portion of acetaminophen is conjugated with either sulfate or glucuronic acid to form water-soluble, readily excreted metabolites and only small amounts of the reactive intermediate, believed to be quinoneimine, are formed by the CYP enzymes (Figure 8.6). 

Although quercetin may stimulate UGT, it inhibits human hepatic sulfation of resveratrol, acetaminophen, dopamine, (-)-salbutamol, minoxidil, and paracetamol in vitro.69,98-101 This inhibition may be chemopreventive, as activation of some promutagens occurs via SULT reactions.68 However, SULT inhibition may also lead to the accumulation of some xenobiotics and possible toxicity. The magnitude of inhibition by quercetin of SULT appears dependent on the isoform because SULT1A3 is less affected than other isoforms, suggesting a tissue-dependent effect of quercetin.69... 

However, the effect of piperine on SULT and flavonoid status across the life cycle remains to be investigated. Induction of phase II metabolism appears to decrease the bioavailability and accelerate the excretion of flavonoids. For example, Siess et al.115 and Walle et al.116 reported flavones induced rat hepatic UGT activity in HepG2 and Caco-2 cells. This induction of UGT enhanced quercetin glucuronidation in Caco-2 cells. In addition to inducing UGT activity, the flavone chrysin inhibits hepatic SULT-mediated sulfation of acetaminophen and minoxidol." The impact of chrysin on the capacity of COMT action toward flavonoids has not been examined. Further, the effect of age on phase II modulation by piperine and chrysin has not been reported. Thus, information on the relationship between age and intake of flavonoids and other phytochemicals that also affect phase II metabolism is required. 

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