Physiological Disposition of Fenoprofen in Man II: Plasma and Urine Pharmacokinetics after Oral and Intravenous Administration

Rubin, Alan; Rodda, Bruce E.; Warrick, Patricia; Ridolfo, Anthony S.; Gruber, Charles M.

doi:10.1002/jps.2600610514

Cited by 34 publications

(4 citation statements)

References 4 publications

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“…It has been shown that high dosage of ibuprofen taken consistently for 4 years results in peak serum concentrations of 50Y100 mg/L (250Y500 mM) (23). Similarly, the plasma levels of fenoprofen achieved by therapeutic doses are in the range of 60 Y200 mM (24). Because ibuprofen and fenoprofen block the transport function of SMCT1 at micromolar concentrations, we speculate that these drugs would effectively compromise the physiologic functions of the transporter in tissues such as the kidney and thyroid gland.…”

Section: Discussionmentioning

confidence: 95%

Interaction of Ibuprofen and Other Structurally Related NSAIDs with the Sodium-Coupled Monocarboxylate Transporter SMCT1 (SLC5A8)

et al. 2006

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Section: Discussionmentioning

confidence: 95%

Interaction of Ibuprofen and Other Structurally Related NSAIDs with the Sodium-Coupled Monocarboxylate Transporter SMCT1 (SLC5A8)

et al. 2006

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“…The individual UGT isozymes tend to exhibit distinct but overlapping patterns of substrate specificity and regulation 3. It has been shown that drugs from many therapeutic classes can undergo glucuronidation, although NSAIDs and analgesics remain the most familiar examples 80–83. Quantitatively, glucuronidation represents the most important route of metabolism for a number of carboxylate drugs.…”

Section: The Physiological Consequences Of Acyl Glucuronide Formationmentioning

confidence: 91%

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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“…": 12 The low renal clearance of unchanged drug and low rate of biotransformation are probably mainly responsible for the slow elimination. ": 12 The low renal clearance of unchanged drug and low rate of biotransformation are probably mainly responsible for the slow elimination.…”

Section: Discussionmentioning

confidence: 99%

Metabolism and kinetics of oxaprozin in normal subjects

Janssen

Jusko

Chiang

et al. 1980

Clin Pharmacol Ther

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Absorption, biotransformation, excretion, and kinetics of oxaprozin (4,5-diphenyl-2-oxazolepropionic acid) were examined in subjects after an oral dose of 14C-oxaprozin alone as well as before, during, and after long-term administration of unlabeled drug. A single dose of 14C-oxaprozin was rapidly absorbed and the unchanged drug was essentially the only labeled substance in plasma. Recovery of radioactivity in excreta, mostly in urine, exceeded 90%. Major biotransformation routes were glucuronidation of the carboxyl group and hydroxylation of the phenyl rings followed by glucuronidation. Administration of unlabeled oxaprozin did not affect the absorption, qualitative, or quantitative metabolite profile, or recovery of 14C-oxaprozin. Following a single dose, the kinetic parameters for 14C and unchanged drug in plasma were nearly the same. A2-compartment model with first-order elimination adequately describes kinetic disposition. The slow clearance (Clp), 0.08 to 0.12 1/hr, was almost entirely due to biotransformation and the plasma half-lifes, which ranged from 49 to 69 hr, reflected the small Clp. The small volume of distribution (VD beta = 8 to 9 1) indicates limited extravascular distribution. Multiple doses of unlabeled drug, especially when given concurrently, increased the Clp of 14C-oxaprozin. This effect is apparently related to decreased binding of high concentrations of oxaprozin to plasma protein. As a result of increased Clp, steady-state levels are only 40% of levels predicted from the single-dose study.

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Physiological Disposition of Fenoprofen in Man II: Plasma and Urine Pharmacokinetics after Oral and Intravenous Administration

Cited by 34 publications

References 4 publications

Interaction of Ibuprofen and Other Structurally Related NSAIDs with the Sodium-Coupled Monocarboxylate Transporter SMCT1 (SLC5A8)

Interaction of Ibuprofen and Other Structurally Related NSAIDs with the Sodium-Coupled Monocarboxylate Transporter SMCT1 (SLC5A8)

Acyl glucuronides: the good, the bad and the ugly

Metabolism and kinetics of oxaprozin in normal subjects

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