Article

Sulfate conjugation in drug metabolism: Role of inorganic sulfate

Federation proceedings 08/1986; 45(8):2235-40.
Source: PubMed

ABSTRACT

Conjugation with sulfate is a major pathway for the biotransformation of phenolic drugs in humans and many animal species. It is a process of limited capacity; the extent of sulfate conjugate formation and the metabolic clearance of drugs subject to conjugation with sulfate depend therefore on the dose, the dosage form, the route of administration, and the rate and duration of administration as well as on the pharmacokinetic parameters of competing processes. The effect of these variables is exemplified by the pharmacokinetics of salicylamide and acetaminophen in humans and rats. In our experience so far, the proximate cause of the nonlinear pharmacokinetics of sulfate conjugation of phenolic drugs is the limited availability and consequent depletion of inorganic sulfate. When this is prevented by direct or indirect (via sulfate donors such as N-acetylcysteine) repletion, the saturability of phenol sulfotransferase (EC 2.8.2.1) activity can become evident. The major mechanism of inorganic sulfate homeostasis is nonlinear renal clearance, which is due largely to saturable renal tubular reabsorption. Systemic depletion of inorganic sulfate secondary to utilization of this anion for the sulfation of drugs affects the availability of sulfate in the central nervous system and may, therefore, modify the disposition of certain neurotransmitters and other endogenous substances that are subject to sulfate conjugation.

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    [Show abstract] [Hide abstract]
    ABSTRACT: Cysteine, via chelation reactions, ameliorates biochemical lesions caused by excessive ingestion of several trace elements. Because oral cysteine per se is considerably more protective than the in vivo metabolic cysteine precursors, methionine or cystine, chelation of cysteine with trace elements likely occurs primarily in the gut, thereby decreasing absorption of both cysteine and the trace element in question. Hence, using copper as an example, orally administered cysteine markedly improves growth and reduces liver copper deposition in chicks or rats fed a high level of inorganic copper. Likewise, excessive copper ingestion impairs sulfur amino acid (SAA) utilization and increases the dietary requirement for SAA. Cobalt and selenium toxicities are also ameliorated by oral cysteine ingestion, with the responses being even more striking than those occurring with copper toxicity. While inorganic arsenic poisonings are generally ameliorated by administering cysteine or a cysteine derivative (e.g., dimercaptopropanol), organic pentavalent arsenic toxicity is exacerbated by cysteine administration. Cysteine in this instance acts as a reducing agent, facilitating conversion of organic pentavalent arsenicals such as roxarsone and arsanilic acid to the more toxic trivalent state.
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