Distribution of gold among plasma fractions in rheumatoid patients undergoing chrysotherapy compared with its distribution in plasma incubated with aurothiomalate in vitro.

Danpure, Christopher J.; Fyfe, David A.; Gumpel, J M

doi:10.1136/ard.38.4.364

Cited by 34 publications

(5 citation statements)

References 21 publications

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“…Peak concentrations of gold following intramuscular administration of sodium aurothiomalate have been recorded after ",,2 hours (Danpure et al 1979;Gottlieb et al 1974;Palmer & Dunckley 1973). Aurothioglucose is formulated as an oily suspension and the peak gold plasma concentration is delayed (Champion et al 1990).…”

Section: Absorption After Intramuscular Administrationmentioning

confidence: 99%

Clinical Pharmacokinetics of Slow-Acting Antirheumatic Drugs

Tett

1993

Clinical Pharmacokinetics

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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, both in controlled clinical trials and in empirical observations from rheumatological practice, delays of several months are reported before full clinical effects are achieved. Variability in response is also characteristic of these agents. Pharmacokinetic factors may partially explain these clinical observations. Delays in the achievement of steady-state concentrations or of concentrations likely to have a therapeutic benefit may occur because of slow drug accumulation. Variable concentrations may arise after standard administered doses because of interindividual pharmacokinetic variability. These factors are likely to contribute to the delay in response and the variable response, respectively. Pharmacokinetics of the antimalarials, hydroxychloroquine and chloroquine, are characterised by extensive tissue sequestration with reported volumes of distribution in the thousands of litres. Both drugs have reported elimination half-lives of greater than 1 month. A 2- to 3-fold range occurs in the fraction of an oral dose absorbed from a tablet formulation. Variable interindividual clearance is also reported. Hydroxychloroquine and chloroquine are administered as racemates. Enantioselective disposition of both compounds occurs, again with notable interindividual variability. Sulphasalazine is split in the large intestine into sulphapyridine, proposed to be the active compound in rheumatoid arthritis, and mesalazine (5-aminosalicylic acid). Sulphapyridine is metabolised partly by acetylation, the rate of which is under genetic control. A wide range of sulphapyridine steady-state concentrations are reported after standard doses of sulphasalazine. The gold complexes are administered either intramuscularly or in an oral form (auranofin). Gold is widely distributed in the body. Very long terminal elimination half-lives and slow accumulation rates are reported. Penicillamine is administered orally. Its bioavailability is variable and may decrease by as much as 70% in the presence of food, antacids and iron salts. Penicillamine forms disulphide bonds with many proteins in the blood 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 the concentration-effect relationships of the SAARDs before the pharmacokinetic characteristics of these drugs can be used effectively to optimise patient therapy.

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Section: Absorption After Intramuscular Administrationmentioning

confidence: 99%

Clinical Pharmacokinetics of Slow-Acting Antirheumatic Drugs

Tett

1993

Clinical Pharmacokinetics

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“…The initial serum half life is 5.5 days [2,3]. Most of the intramuscularly injected gold (>95%) is protein bound, which has been reported to be mainly bound to serum albumin [2,4]. After oral administration of auranofin the serum gold concentrations reach a peak value between 0.2 and 1 μg mL −1 depending on the dose.…”

mentioning

confidence: 99%

In Vitro Distribution of Gold in Serum Proteins after Incubation of Sodium Aurothiomalate and Auranofin with Human Blood and its Pharmacological Significance

Iqbal

Taqi

Arif

et al. 2009

Biol Trace Elem Res

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This study presents a comparative drug-protein, in vitro, binding profile of sodium aurothiomalate and auranofin. It was found that about 40% of total protein-bound gold is attached to albumin after incubation of aurothiomalate with whole blood for 24 h and about 29% of it was with alpha(1)-globulin and the least amount was found with gamma-globulin (6.1%). On the other hand, approximately 84% of the protein-bound auranofin gold attached to globulins of which 51% was found with beta-globulin band. It was almost equally distributed among albumin, alpha(2)-globulin and gamma-globulin, and showed least affinity for alpha(1)-globulin. The gold analyses were performed by standardless instrumental neutron activation method duly validated by use of an established atomic absorption method. The results of this study explain to some extent the difference in, in vivo, pharmacokinetics and pharmacodynamics of the two drugs.

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“…Gold is very largely dissociated from its ligands in the administered drug form and mainly bound to the thiol group (cysteine-34) of albumin to give a circulating reservoir. The gold-albumin complex is longlived in plasma and is also readily formed from gold drugs in vitro [1]. Both aurothiomalate and the protein gold complex have low activity on leukocytes in vitro.…”

Section: Gold Drugsmentioning

confidence: 99%

Is local biotransformation the key to understanding the pharmacological activity of salicylates and gold drugs?

Whitehouse

Graham

1996

Inflamm Res

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It is suggested that some drugs may be converted by inflammatory cells to yield active species. The transformation may be non-enzymatic, although being driven by the enzymatic production of highly reactive species which are normal products of activated leukocytes, such as singlet oxygen, hydrogen peroxide, hypochlorite, hydroxyl radical and nitric oxide. Drugs which may be transformed in this fashion are the anti-rheumatic gold complexes which may be converted either to aurocyanide or to Au(III) complexes by myeloperoxidase in polymorphonuclear leukocytes. Salicylate may also be activated by its oxidation to dihydroxybenzoates although evidence for its transformation is weaker than for the gold complexes.

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Distribution of gold among plasma fractions in rheumatoid patients undergoing chrysotherapy compared with its distribution in plasma incubated with aurothiomalate in vitro.

Cited by 34 publications

References 21 publications

Clinical Pharmacokinetics of Slow-Acting Antirheumatic Drugs

Clinical Pharmacokinetics of Slow-Acting Antirheumatic Drugs

In Vitro Distribution of Gold in Serum Proteins after Incubation of Sodium Aurothiomalate and Auranofin with Human Blood and its Pharmacological Significance

Is local biotransformation the key to understanding the pharmacological activity of salicylates and gold drugs?

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