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PHENYLBUTAZONE PHARMACOKINETICS - STILL A LOT TO LEARN

More than 2S yearsafter phenylbutazone was introducedas a non-steroidalanti-inflammatory agent. basic knowledgeis stillaccumulatingon its pharmacokinetics in man. Phenylbutazone is almost oompletely absorbedafter oral administration. A largefraction of the drug in plasma is bound to proteins, and the drug has a smaUvolume ofdistribution. Phenylbutazone is eliminatedby metabolism, only I % being excreted unchanged in the urine. About 10% of a singledose of phenylbutazone is excreted in bileas metabolites. About 60 % of the urinary metabolites have been identified. A novel type of drug metabolite in man. the C·glucuronKle, is formed bydirectooupling of the pyrazolidine ring of phenylbutazone to glucuronicacid via a C-C bond.Phenylbutazone is oxidisedin a phenyl ringor in theside chain to hydroxylated metabolites. which may undergo subsequent 0­ghcuronidation. After a single dose.C-glueuronidation seems to be the dominant reaction, while oxidation becomes increasinglyimportant after repeated use. Due to different pharmacckinetic propertiesof tl\c metabolites. the C·glucuronides are detected inhighestconcentrations in the urine. while the pharmacologically activecompoundsoxyphenbutazoncand v-hydmxyphenbutazonepredominate in plasma

Its kinetics var y and its effects ha ve not bee n correlated with plasma levelsThe biological(elimination)half-life of phenylbutazone in man is long, with a mean of about 10 hours. and shows largeinter individual and intraindividual variation. The interindividualvariation is largely dueto genetic factors. The intraindividualvariation is dose and time dependent. In an individual there may be several criticaldose levels where a change in the eliminationkinetics takes place. Since there is no correlation between the plasma leveland the clinical or toxic effects of phenylbutazone. thereis at presentno needfor routine monitoring of plasma concentrations of the drug.", ~roakke. L Oinical P!\armaeoll. ineti.-sJ, J69· lS0tSep-Oct 19781[68 refcn:noesl

INPH ARMA 281h Ottobel'. 1978 p16