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Start Over Topic pharmacokinetics Language english Publisher springer-verlag
2,995 results

2. Clinical pharmacokinetics of ketoprofen enantiomers in wild type of Cyp 2c8 and Cyp 2c9 patients with rheumatoid arthritis

Author

Wojciech Romanowski, Franciszek K. Główka, Edmund Grześkowiak, Marta Karaźniewicz-Łada, and Dominika Rogozinska

Subjects
Ketoprofen, Adult, Male, Stereoselective pharmacokinetics, Bioavailability, Capillary zone electrophoresis, Cmax, Cytochrome P450, Urine, Pharmacology, Arthritis, Rheumatoid, Cytochrome P-450 CYP2C8, Pharmacokinetics, medicine, Synovial fluid, Humans, Pharmacology (medical), CYP2C8, CYP2C9, Aged, Cytochrome P-450 CYP2C9, Original Paper, Chemistry, Anti-Inflammatory Agents, Non-Steroidal, Stereoisomerism, Middle Aged, Pharmacogenetics, Female, Aryl Hydrocarbon Hydroxylases, medicine.drug
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.

Published
2011

3. Application of the Convection–Dispersion Equation to Modelling Oral Drug Absorption

Author

Meindert Danhof, Jan Freijer, Teun M. Post, Joost DeJongh, and Bart A. Ploeger

Subjects
Absorption (pharmacology), Adult, Male, Mathematics(all), Time Factors, Neuroscience(all), General Mathematics, Immunology, Normal Distribution, Inverse Gaussian distribution, Administration, Oral, Gastric emptying, Pharmacology, Models, Biological, General Biochemistry, Genetics and Molecular Biology, Pharmacokinetics, Environmental Science(all), Oral administration, Humans, Boundary value problem, NONMEM, General Environmental Science, Convection dispersion, Acetaminophen, Original Paper, Agricultural and Biological Sciences(all), Biochemistry, Genetics and Molecular Biology(all), Chemistry, General Neuroscience, Mechanics, Analgesics, Non-Narcotic, Gastrointestinal Tract, Paracetamol, Computational Theory and Mathematics, Intestinal Absorption, General Agricultural and Biological Sciences, Oral retinoid
Abstract

Models of systemic drug absorption after oral administration are frequently based on a direct or a delayed first-order rate process. In practice, the use of the first-order approach to predict drug concentrations in blood plasma frequently yields a considerable mismatch between predicted and measured concentration profiles. This is particularly true for the upswing of the plasma concentration after oral administration. The current investigation explores an alternative model to describe the absorption rate based on the convection–dispersion equation describing the transport of chemicals through the GI tract. This equation is governed by two parameters, transport velocity and dispersion coefficient. One solution of this equation for a specific set of initial and boundary conditions was used to model absorption of paracetamol in a 22-year-old man after oral administration. The GI-tract passage rate in this subject was influenced by co-administration of drugs that stimulate or delay gastric emptying. The transport-limited absorption function is more accurate in describing the plasma concentration versus time curve after oral administration than the first-order model. Additionally, it provides a mechanistic explanation for the observed curve through the differences in GI-tract passage rate.

Published
2006