Pharmacodynamics, chiral pharmacokinetics, and pharmacokinetic-pharmacodynamic modeling of fenoprofen in patients with diabetes mellitus.

The objective of the present study was to assess the influence of type 1 and type 2 diabetes mellitus on the enantioselective pharmacodynamics and pharmacokinetics of fenoprofen. Patients with diabetes mellitus type 1 (n = 7) or type 2 (n = 7) and healthy volunteers (n = 13) received orally a single 600-mg dose of racemic fenoprofen. Monocompartmental analysis of (+)-(S)-fenoprofen showed a significant difference (P < .05, Kruskal-Wallis test) in area under the curve (AUC) values (153.68 vs 243.50 microg x h/mL) and oral clearance (1.95 vs 1.23 L/h) only between patients with diabetes mellitus type 2 and healthy volunteers. The inhibitory activity of cyclooxygenases was evaluated indirectly by the determination of prostaglandin E2 (COX-2) and thromboxane B2 (COX-1) using the sigmoidal inhibitory Emax model. The patients with type 2 diabetes mellitus presented lower IC50 (3.29 vs 6.0 microg/mL) and g (0.73 vs 2.01) values for COX-1 activity compared to healthy volunteers (P < .05, Kruskal-Wallis test). These results show that diabetes mellitus type 2, but not type 1, influences the pharmacokinetics and pharmacodynamics of (+)-(S)-fenoprofen.

Influence of rheumatoid arthritis in the enantioselective disposition of fenoprofen.

To investigate the influence of rheumatoid arthritis on the stereoselective disposition of fenoprofen administered as a racemic mixture, eight patients with rheumatoid arthritis receiving calcium rac-fenoprofen (200 mg/8 h) and 7 healthy volunteers given single oral dose (600 mg) were investigated. Serial blood samples and urine were collected from zero to 24 h after fenoprofen (FEN) administration. The following differences were observed between the (+)-(S) and (-)-(R)-FEN in the patients with rheumatoid arthritis (means 95% CI, Wilcoxon test, P < 0.05): C(max) 14.1 (12.5-15.8) versus 3.6 (2.5-4.7) microg/ml; AUC(ss) (0-8) 80.5 (67.3-93.7) versus 12.1 (8.8-15.4) microg.h/ml; Cl(T)/f 1.3 (1.0-1.5) versus 9.1 (6.5-11.8) l/h; and t(1/2) 3.1 (2.3-3.9) versus 1.2 (0.8-1.6) h. The Cl(T)/f of (-)-(R)-FEN was reduced in patients with rheumatoid arthritis when compared to healthy volunteers: 9.1 (6.5-11.8) versus 17.4 (13.9-20.9) l/h; P < 0.05 Mann-Whitney test. The administration of rac-FEN as a single dose to healthy volunteers or multiple doses to patients with rheumatoid arthritis resulted in lower Cl(T)/f for the (+)-(S)-FEN. The lower Cl(T)/f of (-)-(R)-FEN observed for patients with rheumatoid arthritis is consistent with lower clearance by inversion, although other metabolic pathways, drug interactions, and bioavailability of the individual enantiomers may also contribute to the difference.

Kinins and cytokines in plasma and cerebrospinal fluid of patients with neuropsychiatric lupus.

OBJECTIVE: To evaluate the kinin system components and selected cytokines in plasma and cerebrospinal fluid (CSF) of patients with neuropsychiatric lupus (NPL). METHODS: We studied 29 women with active NPL and 29 healthy women matched to patients for age. Low (LKg) and high molecular weight kininogen (HKg) and cytokine concentrations [interleukin 1beta (IL-1beta), IL-6, IL-8, IL-10, and tumor necrosis factor-a (TNF-a)] were determined by ELISA. The activities of tissue kallikrein, plasma prekallikrein, and kininase II were assayed by their action on selective substrates. RESULTS: Compared to controls, patients with NPL presented increased plasma and CSF levels of LKg, HKg, and prekallikrein, increased activity of tissue kallikrein and kininase II, and increased levels of IL-6, IL-10, and TNF-a (p < 0.001 each comparison). IL-1beta levels were increased in patient plasma (p < 0.001), whereas plasma IL-8 levels did not differ from controls. IL-1beta and IL-8 were not detected in CSF of patients or controls. CONCLUSION: The increased levels of kininogen fractions, kallikreins, and kininase II in patient plasma and CSF indicate overactivity of the kinin system, suggesting intense kinin production. Since kinins may induce the production of proinflammatory cytokines including IL-1beta, IL-6, and TNF-a, these findings support the participation of kinins and cytokines in the acute manifestations of NPL. Most of the variables evaluated in patients' CSF increased proportionally in relation to plasma levels. In contrast, the activity of tissue kallikrein in patient CSF increased out of proportion to plasma levels, appearing to be locally synthesized in response to brain involvement.