Gallium maltolate (tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III); GM; Figure 14.2) is an orally active complex that is moderately soluble in both aqueous and lipidie solutions (octanol/water partition coefficient of 0.41(8)) and is stable over a pH range of about 5.5-8.0.126 The compound has shown oral gallium bioavailability of at least 25-57% in healthy human subjects, with roughly linear absorption and elimination kinetics following single doses of 100-500 mg and an average maximum serum gallium level (Cmax) of 569(17) ng/ ml at the 500-mg dose.126 Similar results were obtained in elderly subjects with Paget's disease of bone; in these patients it was found that Cmax was 1138(532) ng/kg after 3 days of dosing at 600mg/day.127 Only about 2% of administered gallium was excreted in the urine 72 h after dosing, and no renal toxicity was observed.126 These results strongly suggest that plasma gallium following oral GM administration is nearly all bound to transferrin; in contrast, much of the plasma gallium following iv CGN administration is in the form of gallate, which is rapidly excreted in the urine and may cause renal toxicity.126 The drug appears well tolerated at doses of up to 600mg/day for 3 days.126,127
In animal studies, oral GM has shown efficacy in some rat models of rheumatoid arthritis, in which inflammation and bone degradation were
suppressed (A. Bendele, personal communication, 2004); tuberculosis in guinea pigs;128 and Rhodococcus equi infection in mice.129
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