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Changes in salicylate serum concentration and metabolism during chronic dosing in normal volunteers
Author(s) -
Day Richard O.,
Furst Daniel E.,
Dromgoole Sydney H.,
Paulus Harold E.
Publication year - 1988
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bod.2510090306
Subject(s) - dosing , chemistry , excretion , gentisic acid , glucuronide , salicylic acid , pharmacokinetics , metabolism , bioavailability , absorption (acoustics) , endocrinology , oral administration , medicine , elimination rate constant , steady state (chemistry) , pharmacology , biochemistry , volume of distribution , physics , acoustics
Steady‐state serum salicylic acid (SA) concentrations and the formation rates of salicyluric acid (SU), salicylphenolic glucuronide (SPG), salicylacyl glucuronide (SAG), and gentisic acid (GA), and the excretion rate of unchanged SA were determined in three normal subjects following the administration of a single oral dose of acetylsalicylic acid (ASA) 37 mg kg −1 and during multiple dosing with ASA 56 mg kg −1 day. −1 Steady‐state SA concentrations fell 23 per cent during the 4‐week study period (mean ± SD: 239 ± 35 to 183 ± 23 μg ml −1 ; p < 0.05). Absorption of drug did not decrease during this time. Significant increases in the V max for SU and SPG formation occurred between baseline and during multiple dosing. Mean V max SU increased from 0.93 to 1.68 mg kg −1 h −1 ( p < 0.05) and mean V max SPG increased from 009 to 019 mg kg −1 h −1 ( p< 005). First‐order rate constants for the formation of SAG and GA and for the excretion of unchanged SA did not change significantly between baseline and multiple dosing. The mechanism for the decline in Cp ss SA with time during high‐dose SA therapy is most likely due to the induction of the formation rates of the major metabolites of SA, namely SU and SPG.