Clinical pharmacokinetics of salicylates: a re‐assessment.

Levy, Gerhard

doi:10.1111/j.1365-2125.1980.tb01811.x

Cited by 77 publications

(32 citation statements)

References 26 publications

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“…In postoperative dental pain, salicylate has been reported to have no analgesic activity (Seymour et a!., 1984c), whereas aspirin is highly effective (Seymour and Rawlins, 1982). This study and others summarised by Levy (1980) suggest that the analgesic effects of aspirin are produced primarily by aspirin rather than its hydrolysis product, salicylate. However, aspirin and salicylate possess equipotent anti-inflammatory properties in the treatment of rheumatoid arthritis (Bleckman and Leckner, 1979).…”

Section: Aspirinmentioning

confidence: 80%

Clinical Significance of Esterases in Man

Williams

1985

Clinical Pharmacokinetics

203

103

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Esterases, hydrolases which split ester bonds, hydrolyse a number of compounds used as drugs in humans. The enzymes involved are classified broadly as cholinesterases (including acetylcholinesterase), carboxylesterases, and arylesterases, but apart from acetylcholinesterase, their biological function is unknown. The acetylcholinesterase present in nerve endings involved in neurotransmission is inhibited by anticholinesterase drugs, e.g. neostigmine, and by organophosphorous compounds (mainly insecticides). Cholinesterases are primarily involved in drug hydrolysis in the plasma, arylesterases in the plasma and red blood cells, and carboxylesterases in the liver, gut and other tissues. The esterases exhibit specificities for certain substrates and inhibitors but a drug is often hydrolysed by more than one esterase at different sites. Aspirin (acetylsalicylic acid), for example, is hydrolysed to salicylate by carboxylesterases in the liver during the first-pass. Only 60% of an oral dose reaches the systemic circulation where it is hydrolysed by plasma cholinesterases and albumin and red blood cell arylesterases. Thus, the concentration of aspirin relative to salicylate in the circulation may be affected by individual variation in esterase levels and the relative roles of the different esterases, and this may influence the overall pharmacological effect. Other drugs have been less extensively investigated than aspirin and these include heroin (diacetylmorphine), suxamethonium (succinylcholine), clofibrate, carbimazole, procaine and other local anaesthetics. Ester prodrugs are widely used to improve absorption of drugs and in depot preparations. The active drug is released by hydrolysis by tissue carboxylesterases. Individual differences in esterase activity may be genetically determined, as is the case with atypical cholinesterases and the polymorphic distribution of serum paraoxonase and red blood cell esterase D. Disease states may also alter esterase activity.

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Section: Aspirinmentioning

confidence: 80%

Clinical Significance of Esterases in Man

Williams

1985

Clinical Pharmacokinetics

203

103

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“…The pharmacokinetics of aspirin and its active breakdown product salicylic acid in man are now reasonably well characterised and the available information has been summarised in recent reviews (Levy, 1979(Levy, , 1980. In this discussion the terms salicylic acid and salicylate will be used interchangeably.…”

Section: Aspirin and Salicylic Acidmentioning

confidence: 98%

Clinical Pharmacokinetics of Non-steroidal Anti-inflammatory Drugs

Verbeeck

Blackburn

Loewen

1983

Clinical Pharmacokinetics

212

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The number of non-steroidal anti-inflammatory drugs (NSAIDs) available for clinical use has dramatically increased during the last decade. As a general rule, NSAIDs are well absorbed from the gastrointestinal tract, with the exception of aspirin (and possibly diclofenac, tolfenamic acid and fenbufen) which undergoes presystemic hydrolysis to form salicylic acid. Concomitant administration of NSAIDs with food or antacids may in some cases lead to delayed or even reduced absorption. The NSAIDs are highly bound to plasma proteins (mainly albumin), which limits their body distribution to the extracellular spaces. Apparent volumes of distribution of NSAIDs are, therefore, very low and usually less than 0.2 L/kg. The elimination of these drugs depends largely on hepatic biotransformation; renal excretion of unchanged drugs is usually small (less than 5% of the dose). Total body clearance is low and for most NSAIDs is less than 200 ml/min. The effect of age and disease on the disposition of NSAIDs has not been extensively studied. Due to the central role of the liver in the overall elimination of the majority of these compounds, hepatic disease will most likely lead to a significant alteration in their pharmacokinetic behaviour. NSAIDs have been reported to be involved in numerous pharmacokinetic drug interactions. Aspirin decreases the plasma concentrations of many other NSAIDs, although the clinical significance of this is uncertain. Due to the extremely high plasma protein binding of NSAIDs (around 99% in many cases), competition for the same binding sites on plasma proteins may be at least partly responsible for some interactions of NSAIDs with other highly bound drugs; however, another mechanism such as decreased metabolism or decreased urinary elimination is usually involved as well. The most important interactions with NSAIDs are those involving the oral anticoagulants and oral hypoglycaemic agents, though not all NSAIDs have been found to interact with these drugs. In clinical practice, there appear to be no clear-cut guidelines to assist the clinician in the selection of the most appropriate drug for an individual patient. The selection of an anti-inflammatory drug should be based on clinical experience, patient convenience (e.g. once or twice daily dosage schedule), side effects and cost. Since a marked interindividual variability exists in the clinical response to a given NSAID, clinicians prescribing these agents may try several of them sequentially until an adequate response is obtained.

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“…Levels greater than 100 mg/dL are potentially life-threatening [128]. At higher doses, levels of free salicylates increase exponentially as serum protein binding becomes saturated [129]. The half-life of salicylates increases from 2 to 4 hours at therapeutic levels to 15 to 29 hours at toxic doses in children [130,131].…”

Section: Overviewmentioning

confidence: 99%