Tolmetin Glycine Category

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1059 (6.6), with glycine as the pro-moiety. Careful pharmacological studies in a variety of animal species showed that midodrine had a markedly longer duration of action than ST 1059 and showed good efficacy after oral administration. It was, therefore, concluded that the pressor agent ST 1059 was liberated enzymatically from midodrine, a well-absorbed 'transport form'.

The glycine amide of tolmetin (6.7) functions as a prodrug and was shown to be orally more potent than tolmetin as an inhibitor of adjuvant arthritis in the female Lewis rat [25]. The superiority of tolmetin glycine amide relative to tolmetin in these tests was demonstrated by inhibition of paw swelling and reduction of degenerative bone changes in an animal model of human chronic rheumatoid arthritis. These properties were not evident after oral administration of equimolar mixtures of tolmetin sodium and glycine. Pharmacoki-netic analyses revealed that tolmetin glycine amide was completely absorbed orally and hydrolyzed to tolmetin in the adjuvant arthritic rat. The combined effects of oral absorption, distribution, and hydrolysis of tolmetin glycine amide produced lower plasma peak levels of tolmetin than an equivalent dose of tolmetin sodium, but plasma concentrations were sustained for a longer period and contributed to an apparent increase in potency. Furthermore, tol-metin glycine amide had a decreased propensity to cause gastrointestinal irritation compared to tolmetin sodium. Several additional amino acid amides of tolmetin were similar to the glycine amide in exhibiting increased potency and reduced gastrointestinal toxicity in comparison to equimolar doses of tolmetin sodium.

Interestingly, the favorable results obtained with tolmetin glycine amide were not shared by indomethacin glycine amide [25].

Traceable Fall Leaves

N-acetyl-Met

Fig. 6.6. Pathways of hydrolytic bioactivation of docarpamine (6.8) to liberate dopamine (6.9)

N-acetyl-Met

Fig. 6.6. Pathways of hydrolytic bioactivation of docarpamine (6.8) to liberate dopamine (6.9)

Docarpamine (6.8, Fig. 6.6) was developed as a potential orally active prodrug of dopamine (6.9, Fig. 6.6) to be used in the treatment of renal insufficiency, congestive heart failure, and some types of shock [26][27]. Indeed, dopamine itself is active only by intravenous infusion since it undergoes extensive inactivation by first-pass metabolism. Following oral administration to rats and dogs, the main pathway of metabolism in the small intestine was hydrolysis of the two ethoxycarbonyl pro-moieties esterifying the catechol group. Amide hydrolysis to liberate the V-acetylmethionine pro-moiety was a minor pathway. In the liver, ester hydrolysis was, again, a major pathway, but so was hydrolysis of the amide linkage (Fig. 6.6). Clinical studies have confirmed the safety and efficacy of docarpamine in patients undergoing cardiac surgery [28].

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