title: Clinical pharmacokinetics of ketoprofen enantiomers in wild type of Cyp 2c8 and Cyp 2c9 patients with rheumatoid arthritis.
abstract: Pharmacokinetics of ketoprofen (KTP) enantiomers has been studied in patients with rheumatoid arthritis (RA) following administration of a single oral dose of 100 mg rac-KTP during multidrug therapy taking into consideration the genotype of RA patients Concentrations of (-)-R and (+)-S enantiomers of KTP in plasma, urine and synovial fluid samples were determined using a validated HPCE method. The genotype of the patients was analyzed using PCR-RFLP method to determine the polymorphic variants of genes coding CYP2C8 and CYP2C9 isoenzymes. The levels of KTP enantiomers in synovial fluid at 4 h following administration were insignificantly greater [(-)-R = 1.34 ± 0.91 mg/L; (+)-S = 1.38 ± 0.91 mg/L] than in plasma [(-)-R = 1.15 ± 0.95 mg/L; (+)-S = 1.22 ± 0.95 mg/L]. The values of AUC(0-∞) were 11.89 ± 5.00 and 10.92 ± 4.10 mg h/L for (-)-R and (+)-S enantiomer, respectively, and were lower compared with data obtained in healthy volunteers following administration of the same dose of rac-KTP. But, no statistically significant differences were observed also for C (max), Cl, V (d), t (0.5) and MRT of KTP enantiomers. The total percentage of unchanged KTP eliminated with urine of RA patients was in the range of 30-50% of the administered dose. Though RA patients represented the same wild genotype, quite significant variabilities (Cl((-)-R ) = 2.37-13.50 L/h and Cl((+)-S ) = 2.44-9.90 L/h) existed in the pharmacokinetics parameters of KTP. We concluded that KTP data obtained from healthy volunteers cannot be sufficient to predict disposition of KTP enantiomers in RA patients, especially when undergoing long-term multidrug therapy.
authors.affiliation: Depatment of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland. glowka@ump.edu.pl
authors.forename: Franciszek
authors.initials: F
authors.lastname: Główka
authors.forename: Marta
authors.initials: M
authors.lastname: Karaźniewicz-Łada
authors.forename: Edmund
authors.initials: E
authors.lastname: Grześkowiak
authors.forename: Dominika
authors.initials: D
authors.lastname: Rogozinska
authors.forename: Wojciech
authors.initials: W
authors.lastname: Romanowski
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D006801:Humans; D007660:Ketoprofen / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D013237:Stereoisomerism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007660:Ketoprofen; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8