Effect of dose on the glucuronidation and sulphation kinetics of diflunisal in man: single dose studies.

Loewen, G R; Herman, RJ; Ross, S.; Verbeeck, Roger K.

doi:10.1111/j.1365-2125.1988.tb03360.x

Cited by 31 publications

(21 citation statements)

References 18 publications

(22 reference statements)

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“…Meffin et al (1983) studied the multiple dose pharmacokinetics of diflunisal in patients with osteoarthritis. They found that the dose-dependent reduction in the oral clearance (Loewen et al, 1988), which is in contrast to the results obtained by Meffin et al (1983). Since steady state plasma concentrations of diflunisal following daily doses of 1000 mg fall within the.…”

Section: Discussioncontrasting

confidence: 54%

“…In single-dose studies we found no evidence of saturation of the sulphation of diflunisal (Loewen et al, 1988). The present results show that even after multiple dosing, sulphation of diflunisal is not saturated and thus follows linear kinetics.…”

Section: Discussionmentioning

confidence: 45%

“…Previous studies have shown that the pharmacokinetics of diflunisal are concentrationdependent (Davies, 1983;Loewen et al, 1988;Meffin et al, 1983). Following administration of single doses, this concentration-dependency seemed to arise mainly from saturation of the formation of the acyl glucuronide (Loewen et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

“…Following administration of single doses, this concentration-dependency seemed to arise mainly from saturation of the formation of the acyl glucuronide (Loewen et al, 1988). Meffin et al (1983) studied the multiple dose pharmacokinetics of diflunisal in patients with osteoarthritis.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous study we showed that the pharmacokinetics of diflunisal were dose-dependent following administration of single doses (100-1000 mg) (Loewen et al, 1988). The gradual decrease in plasma diflunisal clearance following administration of increasing single doses seemed to be due to saturation of the formation of the acyl glucuronide.…”

Section: Introductionmentioning

confidence: 99%

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The effect of multiple dosage on the kinetics of glucuronidation and sulphation of diflunisal in man.

Verbeeck

Loewen

MacDonald

et al. 1990

Brit J Clinical Pharma

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1 The single (250 and 500 mg) and multiple dose (250 and 500 mg twice daily for 15 days) pharmacokinetics of diflunisal were compared in young volunteers. 2 The plasma clearance of diflunisal was lowered significantly after multiple dose administration (5.2 ± 1.2 and 4.2 ± 0.7 ml min-' for the 250 and 500 mg twice daily regimens, respectively) as compared with single dose administration (11.4 ± 3.1 and 9.9 + 2.0 ml min-' for the 250 and 500 mg single doses, respectively).3 The partial metabolic clearances of diflunisal by acyl and phenolic glucuronide formation were lowered significantly (> 50%) after multiple dose administration. 4 The urinary recovery of diflunisal sulphate increased as a function of dose: 6.1 ± 2.8 and 9.1 ± 3.5% following the 250 and 500 mg single dose, respectively, and 10.9 ± 3.1 and 15.9 ± 3.6% following the 250 and 500 mg twice daily regimens. The partial metabolic clearance of diflunisal by sulphate conjugation was unchanged following multiple dose administration. 5 The plasma protein binding of diflunisal was concentration-dependent. Analysis of unbound plasma clearances of diflunisal showed that its total plasma clearance following 500 mg twice daily was affected by both saturable glucuronidation and concentrationdependent plasma binding.

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Section: Discussioncontrasting

confidence: 54%

Section: Discussionmentioning

confidence: 45%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The effect of multiple dosage on the kinetics of glucuronidation and sulphation of diflunisal in man.

Verbeeck

Loewen

MacDonald

et al. 1990

Brit J Clinical Pharma

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Principles of Drug Metabolism

Dalvie

Testa

2021

Burger's Medicinal Chemistry and Drug Discovery

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Metabolism is a complex process that involves enzymatic modification of drugs and xenobiotics and is one of the most important determinants of their fate in the body. Although the drug metabolism is considered a process of detoxification, the products of metabolism can play an important role in the pharmacology and toxicology of the parent drug. Studying the metabolism of newly synthesized molecules is a valuable strategy that allows one to identify the underlying problems, such as “soft spots,” or metabolic activation, that affect the systemic exposure of a molecule and safety and efficacy. Early investigative metabolism of new compounds has helped in assessing the bioactivation potential of these candidates and thus, avoid reactive metabolites or put mitigation strategies in place. Metabolism can also lead to pharmacologically active metabolites. These metabolites can have superior pharmacological, pharmacokinetic, and safety profiles compared to their parent drug and can therefore be developed as drugs. This chapter provides an overview of the enzymes involved in the metabolism of xenobiotics and the different metabolic pathways. An attempt has been made to illustrate these principles with pertinent example with a brief review of topics of potential interests to aspiring medicinal chemists namely, the factors that may influence biotransformation or applications to predict the sites of metabolism. While the medicinal chemists are not expected to possess a deep knowledge of the mechanistic aspects, the hope is that the principles outlined in this chapter will assist them in designing a better drug.

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Acyl glucuronides: the good, the bad and the ugly

Regan

Maggs

Hammond

et al. 2010

Biopharm & Drug Disp

166

145

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Acyl glucuronidation is the major metabolic conjugation reaction of most carboxylic acid drugs in mammals. The physiological consequences of this biotransformation have been investigated incompletely but include effects on drug metabolism, protein binding, distribution and clearance that impact upon pharmacological and toxicological outcomes. In marked contrast, the exceptional but widely disparate chemical reactivity of acyl glucuronides has attracted far greater attention. Specifically, the complex transacylation and glycation reactions with proteins have provoked much inconclusive debate over the safety of drugs metabolised to acyl glucuronides. It has been hypothesised that these covalent modifications could initiate idiosyncratic adverse drug reactions. However, despite a large body of in vitro data on the reactions of acyl glucuronides with protein, evidence for adduct formation from acyl glucuronides in vivo is limited and potentially ambiguous. The causal connection of protein adduction to adverse drug reactions remains uncertain. This review has assessed the intrinsic reactivity, metabolic stability and pharmacokinetic properties of acyl glucuronides in the context of physiological, pharmacological and toxicological perspectives. Although numerous experiments have characterised the reactions of acyl glucuronides with proteins, these might be attenuated substantially in vivo by rapid clearance of the conjugates. Consequently, to delineate a relationship between acyl glucuronide formation and toxicological phenomena, detailed pharmacokinetic analysis of systemic exposure to the acyl glucuronide should be undertaken adjacent to determining protein adduct concentrations in vivo. Further investigation is required to ascertain whether acyl glucuronide clearance is sufficient to prevent covalent modification of endogenous proteins and consequentially a potential immunological response.

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Effect of dose on the glucuronidation and sulphation kinetics of diflunisal in man: single dose studies.

Cited by 31 publications

References 18 publications

The effect of multiple dosage on the kinetics of glucuronidation and sulphation of diflunisal in man.

The effect of multiple dosage on the kinetics of glucuronidation and sulphation of diflunisal in man.

Principles of Drug Metabolism

Acyl glucuronides: the good, the bad and the ugly

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