The combillalioll trimethoprim-sulphametllOxazole (co-trimoxazole) is used c1illical(v for the treatmelll of a \'Oriety of illfectiolls due to Gram-positil'e alld Gram-llegatipe orgallisms; particular(I' for urillary alld respiratory tract il(fectiolls While both trimet/wprim alld sulphametlwxazole are mainly bacteriostatic when used alone. their combilled effect tellds to be bactericidal. SYllergism is due to sequelltial blockade at two separate steps ill bacterial folate metabolism. resultillg ill illhibitioll of deoxyribollllcleic acid sylllhesis.The optimum collcelltralioll ratio of trimetllOprim:sulphametllOxazole {i)r a bactericidal effect paries betwf:ell 1:5 alld I :40. which is collsistellt with their relatipe minimum inhibitory concellIration (MIC) palues against susceptible organisms. The combination is administered principal(I' by the oral route. although it is also giwlI parellleralb' and rectalb'. A single oral dose of 160mg trimetllOprim and 800mg sulphametllOxazole gives peak sertlm lel'els at approximately 411 of 1.2 to 2}Jg / ml trimetllOprim alld 26 to 63}Jg / ml sulpl1ametl1oxazole. After repeated 12 -I/Our(v doses. minimum sertlm /el'e/s are 1.3 to 2.8}Jg / ml and 32 to 63}Jg/ ml {i)r trinll;'tllOprim and slllphametllOxazole respectil'e(I'. The high con celli ration of slllphametllOxazole in serum re/atil'e to that of trimethoprim is dlle to the greater tisslle penetration of trimetllOprim. The high sulphametlwxazole:trimethoprim cOllcentration ratio in serum does Iwt always occur in extral'ascular tissues. However, this is partially compensated {i)r by tile higl1 bacteriostatic actil'ity of trimethoprim alone in tissues.The 2 compounds are bound to plasma proteins to similar extellIs. Both trimethoprim and sulphamethoxazole obey first order absorption. distributioll. alld elimination killetics. The disposition t!f sulphamethoxazole in the body after oral doses has been described ill .terms of onecompartment model kinetics, while both Olle-compartmelll and lII'o-compartment model kinetics hOl'e been IIsed to describe the disposition of trimetllOprim.Both compoullds are cleared from the body predominantly via the kidneys. slIlphametllOxazole being excreted mainly ill the acetylated {i)rm. Average elimillatioll half-lives of trimetllOprim and slIlphamethoxazole are II alld 9h respectively, althollgh there is considerable illdividual variatioll ill these I'ailles. The clearance of both compoullds is not marked(1' affected by declining rellal function until creatinille clearance falls be/ow 30ml/ min. /n severe renal failure, the elimination ha(f-/ives of both drugs may increase to 45 to 60h and adJustment of dosage is necessary to avoid renal toxicity. Both trimetlwprim alld sulphamet!Joxazole appear
Plasma levels of penicillamine, urinary recovery of penicillamine and its oxidized metabolites, and urinary excretion of copper were examined after single 500-mg oral doses of penicillamine to six healthy men. Penicillamine was given after an overnight fast, a standard breakfast, and after antacid and ferrous sulfate. Following the fasting dose, the mean peak plasma level of 3.05 micrograms/ml developed at 3.8 hr and the drug was cleared from plasma with a t1/2 of 2.1 hr. Penicillamine levels were reduced to 52%, 35%, and 66% of those from the fasting dose after food, ferrous sulfate, and antacid. The rates of penicillamine appearance and disappearance from plasma were essentially treatment independent. There were good correlations between urinary recovery of total penicillamine (r = 0.875), between urinary copper excretion (r = 0.758) and the penicillamine plasma concentration AUCs. The availability of oral penicillamine is very susceptible to interactions with other substances. Further studies may be necessary to assess the full clinical significance of these interactions.
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