These findings indicate that the oxisuran alcohols
(oxisuranols) are pharmacologically active and contribute substantially to the overall immunosuppressive effect of the parent drug. The sulfoxide group in oxisuran is chiral, by virtue of the lone pair of electrons on sulfur. Therefore, reduction of oxisuran leads to diastereomeric alcohols.
Reduction of a,jS-unsaturated ketones results in reduction not only of the ketone group but of the carbon-carbon double bond as well. Steroidal drugs often fall into this class, including norethindrone, a synthetic progestin found in many oral contraceptive drug combinations. In women, the major plasma and urinary metabolite of norethindrone is the 3S,5jS-tetrahydro derivative.307
Ketones resulting from metabolic oxidative deamination processes are also susceptible to reduction. For instance, rabbit liver microsomal preparations metabolize amphetamine to phenylacetone, which is reduced subsequently to 1-phenyl-2-propanol.308 In humans, a minor urinary metabolite of ( — )-ephedrine has been identified as the diol derivative formed from keto reduction of the oxidatively deaminated product 1-hydroxy-1-phenylpropan-2-one.309
The reduction of aromatic nitro and azo xenobiotics leads to aromatic primary amine metabolites.286 Aromatic nitro compounds are reduced initially to the nitroso and hydroxylamine intermediates, as shown in the following metabolic sequence:
Azo reduction, however, is believed to proceed via a hydrazo intermediate (-NH-NH-) that subsequently is cleaved reductively to yield the corresponding aromatic amines:
Bioreduction of nitro compounds is carried out by NADPH-dependent microsomal and soluble nitro reductases present in the liver. A multicomponent hepatic microsomal
reductase system requiring NADPH appears to be responsible for azo reduction.310-312 In addition, bacterial reductases present in the intestine can reduce nitro and azo compounds, especially those that are absorbed poorly or excreted mainly in the bile.313314
Various aromatic nitro drugs undergo enzymatic reduction to the corresponding aromatic amines. For example, the 7-nitro benzodiazepine derivatives clonazepam and nitrazepam are metabolized extensively to their respective 7-amino metabolites in humans.315,316 The skeletal muscle relaxant dantrolene (Dantrium) also reportedly undergoes reduction to aminodantrolene in humans.317,318
For some nitro xenobiotics, bioreduction appears to be a minor metabolic pathway in vivo, because of competing oxidative and conjugative reactions. Under artificial anaerobic in vitro incubation conditions, however, these same nitro xenobiotics are enzymatically reduced rapidly. For example, most of the urinary metabolites of metronidazole found in humans are either oxidation or conjugation products. Reduced metabolites of metronidazole have not been detected.319 When incubated anaerobically with guinea pig liver preparations, however, metronidazole undergoes considerable nitro reduction.320
Bacterial reductase present in the intestine also tends to complicate in vivo interpretations of nitro reduction. For example, in rats, the antibiotic chloramphenicol is not reduced in vivo by the liver but is excreted in the bile and, subsequently, reduced by intestinal flora to form the amino metabolite.321,322
The enzymatic reduction of azo compounds is best exemplified by the conversion of sulfamidochrysoidine (Prontosil) to the active sulfanilamide metabolite in the liver.323 This reaction has historical significance, for it led to the discovery of sulfanilamide as an antibiotic and eventually to the development of many of the therapeutic sulfonamide drugs. Bacterial reductases present in the intestine play a significant role in reducing azo xenobiotics, particularly those that are absorbed poorly.313,314 Accordingly, the two azo dyes tartrazine324,325 and amaranth326 have poor oral absorption because of the many polar and ionized zsulfonic acid groups present in their structures.
Therefore, these two azo compounds are metabolized primarily by bacterial reductases present in the intestine. The importance of intestinal reduction is further revealed in the metabolism of sulfasalazine (formerly salicylazosul-fapyridine, Azulfidine), a drug used in the treatment of ulcerative colitis. The drug is absorbed poorly and undergoes reductive cleavage of the azo linkage to yield sulfapyridine and 5-aminosalicylic acid.327,328 The reaction occurs primarily in the colon and is carried out principally by intestinal bacteria. Studies in germfree rats, lacking intestinal flora, have demonstrated that sulfasalazine is not reduced to any appreciable extent.329
Several minor reductive reactions also occur. Reduction of N-oxides to the corresponding tertiary amine occurs to some extent. This reductive pathway is of interest because several tertiary amines are oxidized to form polar and water-soluble N-oxide metabolites. If reduction of N-oxide metabolites occurs to a significant extent, drug elimination of the parent tertiary amine is impeded. N-Oxide reduction often is assessed by administering the pure synthetic N-oxide in vitro or in vivo and then attempting to detect the formation of the tertiary amine. For example, imipramine N-oxide undergoes reduction in rat liver preparations.330
Reduction of sulfur-containing functional groups, such as the disulfide and sulfoxide moieties, also constitutes a minor reductive pathway. Reductive cleavage of the disulfide bond in disulfiram (Antabuse) yields N,N-diethyldithiocarbamic acid (free or glucuronidated) as a major metabolite in humans.331,332 Although sulfoxide functionalities are oxidized mainly to sulfones (-SO2-), they sometimes undergo reduction to sulfides. The
Sulindac Sulindac Sulfide
importance of this reductive pathway is seen in the metabolism of the anti-inflammatory agent sulindac (Clinoril). Studies in humans show that sulindac undergoes reduction to an active sulfide that is responsible for the overall antiinflammatory effect of the parent drug.333,334 Sulindac or its sulfone metabolite exhibits little anti-inflammatory activity. Another example of sulfide formation involves the reduction of DMSO to dimethyl sulfide. In humans, DMSO is metabolized to a minor extent by this pathway. The characteristic unpleasant odor of dimethyl sulfide is evident on the breath of patients who use this agent.335
(Atromid-S) yields ^-chlorophenoxyisobutyric acid (CPIB) as the major plasma metabolite in humans.344 Studies in rats indicate that the free acid CPIB is responsible for clofibrate's hypolipidemic effect.345
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