CLINICAL PHARMACOKINETICS OF SLOW-ACTING ANTIRHEUMATIC DRUGS

The pharmacokinetics of the slow acting antirheumatic drugs (SAARDs), hydroxychloroquine, chloroquine, penicillamine, the gold complexes and sulphasalazine, in humans have been studied. For all these drugs, bot h in controlled clinical trials and in empirical observations from rhe umatological practice, delays of several months are reported before fu ll clinical effects are achieved. Variability in response is also char acteristic of these agents. Pharmacokinetic factors may partially expl ain these clinical observations. Delays in the achievement of steady-s tate concentrations or of concentrations likely to have a therapeutic benefit may occur because of slow drug accumulation. Variable concentr ations may arise after standard administered doses because of interind ividual pharmacokinetic variability. These factors are likely to contr ibute to the delay in response and the variable response, respectively . Pharmacokinetics of the antimalarials, hydroxychloroquine and chloro quine, are characterised by extensive tissue sequestration with report ed volumes of distribution in the thousands of litres. Both drugs have reported elimination half-lives of greater than 1 month. A 2- to 3-fo ld range occurs in the-fraction of an oral dose absorbed from a tablet formulation. Variable interindividual clearance is also reported. Hyd roxychloroquine and chloroquine are administered as racemates. Enantio selective disposition of both compounds occurs, again with notable int erindividual variability. Sulphasalazine is split in the large intesti ne into sulphapyridine, proposed to be the active compound in rheumato id arthritis, and mesalazine (5-aminosalicylic acid). Sulphapyridine i s metabolised partly by acetylation, the rate of which is under geneti c control. A wide range of sulphapyridine steady-state concentrations are reported after standard doses of sulphasalazine. The gold complexe s are administered either intramuscularly or in an oral form (auranofi n). Gold is widely distributed in the body. Very long terminal elimina tion half-lives and slow accumulation rates are reported. Penicillamin e is administered orally. Its bioavailability is variable and may decr ease by as much as 70% in the presence of food, antacids and iron salt s. Penicillamine forms disulphide bonds with many proteins in the bloo d and tissues, creating potential slow release reservoirs of the drug. Like the other SAARDs, gold complexes and penicillamine are found in a wide range of blood concentrations after administration in standard doses to different individuals. More research must be conducted into t he concentration-effect relationships of the SAARDs before the pharmac okinetic characteristics of these drugs can be used effectively to opt imise patient therapy.