title: Diclofenac plasma protein binding: PK-PD modelling in cardiac patients submitted to cardiopulmonary bypass.
abstract: Twenty-four surgical patients of both sexes without cardiac, hepatic, renal or endocrine dysfunctions were divided into two groups: 10 cardiac surgical patients submitted to myocardial revascularization and cardiopulmonary bypass (CPB), 3 females and 7 males aged 65 +/- 11 years, 74 +/- 16 kg body weight, 166 +/- 9 cm height and 1.80 +/- 0.21 m2 body surface area (BSA), and control, 14 surgical patients not submitted to CPB, 11 female and 3 males aged 41 +/- 14 years, 66 +/- 14 kg body weight, 159 +/- 9 cm height and 1.65 +/- 0.16 m2 BSA (mean +/- SD). Sodium diclofenac (1 mg/kg, im Voltaren 75 twice a day) was administered to patients in the Recovery Unit 48 h after surgery. Venous blood samples were collected during a period of 0-12 h and analgesia was measured by the visual analogue scale (VAS) during the same period. Plasma diclofenac levels were measured by high performance liquid chromatography. A two-compartment open model was applied to obtain the plasma decay curve and to estimate kinetic parameters. Plasma diclofenac protein binding decreased whereas free plasma diclofenac levels were increased five-fold in CPB patients. Data obtained for analgesia reported as the maximum effect (EMAX) were: 25% VAS (CPB) vs 10% VAS (control), P < 0.05, median measured by the visual analogue scale where 100% is equivalent to the highest level of pain. To correlate the effect versus plasma diclofenac levels, the EMAX sigmoid model was applied. A prolongation of the mean residence time for maximum effect (MRTEMAX) was observed without any change in lag-time in CPB in spite of the reduced analgesia reported for these patients, during the time-dose interval. In conclusion, the extent of plasma diclofenac protein binding was influenced by CPB with clinically relevant kinetic-dynamic consequences.
authors.affiliation: Laboratório de Pesquisa, Faculdade de Medicina, Universidade de São Paulo, Brasil.
authors.forename: J O
authors.initials: JO
authors.lastname: Auler Júnior
authors.forename: E B
authors.initials: EB
authors.lastname: Espada
authors.forename: E
authors.initials: E
authors.lastname: Crivelli
authors.forename: T B
authors.initials: TB
authors.lastname: Quintavalle
authors.forename: A
authors.initials: A
authors.lastname: Kurata
authors.forename: N A
authors.initials: NA
authors.lastname: Stolf
authors.forename: A M
authors.initials: AM
authors.lastname: Issy
authors.forename: O E
authors.initials: OE
authors.lastname: Paschoa
authors.forename: M
authors.initials: M
authors.lastname: Danhof
authors.forename: D D
authors.initials: DD
authors.lastname: Breimer
authors.forename: D A
authors.initials: DA
authors.lastname: Chamone
authors.forename: S R
authors.initials: SR
authors.lastname: Santos
mesh_terms: D000328:Adult; D000368:Aged; D000698:Analgesia; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D002315:Cardiopulmonary Bypass / Q000534:rehabilitation*; D004008:Diclofenac / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011485:Protein Binding / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac