Pharmacokinetics of Diclofenac Sodium in Chronic Active Hepatitis and Alcoholic Cirrhosis

Abstract

The objective of this study was to assess the pharmacokinetics of diclofenac sodium and its five metabolites following administration of a 150 mg oral dose to healthy subjects and patients with either chronic active hepatitis of varying morphology or alcoholic cirrhosis. Six healthy subjects, 6 chronic active hepatitis patients, and 6 alcoholic cirrhosis patients were enrolled in this prospective, open-label, parallel study. Blood samples were drawn at 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 312, and 480 hours, and urine samples were collected for 144 hours after administration of a single oral dose of diclofenac sodium. The mean area under the serum concentration-time curve extrapolated to infinity, oral clearance, half-life, maximal concentration, and time to peak concentration for diclofenac and its metabolites were determined and compared using analysis of variance. Cirrhotics had a mean +/- SD diclofenac AUC value (19,114 +/- 6806 ng.h/ml) significantly different (p < 0.02) from hepatitis patients (6071 +/- 1867 ng.h/ml) and healthy subjects (7008 +/- 2006 ng.h/ml), whereas healthy subjects and hepatitis patients had similar values. Comparable results were found for 4'-hydroxydiclofenac. The AUC values for 3'-hydroxydiclofenac and 3'-hydroxy-4'methoxydiclofeanc were significantly different when healthy subjects were compared to cirrhotics. However, hepatitis subjects were not significantly different from either group. The results indicate that hepatitis does not alter the pharmacokinetics of diclofenac. Alcoholic cirrhosis increased the mean diclofenac AUC approximately three times compared to normal subjects, indicating that one-third of the usual dose in cirrhotics would produce equivalent AUC values in normal subjects and subjects with alcoholic cirrhosis. However, since pharmacodynamic measurements were not made and no increase in untoward or side effects was noted in the alcoholic cirrhosis patients after a single dose, maintenance doses should be titrated to patients response.

Pharmacokinetics of diclofenac in rats intoxicated with CCL4, and in the regenerating liver

“…group. Diclofenac is a medium hepatic extraction ratio drug [16] and undergoes considerable first-pass metabolism. Therefore, its oral bioavailability is importantly affected [2,6,46,47].…”

“…The extent of absolute oral bioavailability is influenced by the hepatic first-pass effect [16]. In addition, portalvenous flow could be diminished, due to inflammation caused by necrosis in acute CCl 4 intoxication contributing to a diminution of the absorption of the drug and the total bioavailability.…”

“…The alterations in the pharmacokinetics of diclofenac that occur with hepatic disease result in complex changes for total concentrations and drug response [5]. It seems that alcoholic cirrhosis in humans increased the extent of absolute oral bioavailability of this drug approximately three times compared with normal subjects, indicating that one-third of the usual dose in cirrhotics would produce equivalent total bioavailability values in normal subjects and subjects with alcoholic cirrhosis [16], but with moderate degrees of hepatic impairment, there is a decrease in the clearance of drugs or active metabolites [17].…”

Validated LC-MS/MS method for the determination of the nonsteroidal anti-inflammatory drug (NSAID) Diclofenac from human plasma

“…450-600 ng/ml, after administration of a 25 mg dose. [2,9,10] A summary of main results of validation batches is presented in Table 1. The validated calibration range was 3.9-1194 ng/ml.…”

Influence of Subinhibitory Concentrations of Protein-Synthesis-Inhibiting Antibiotics on Production and Release of the Pneumococcal Virulence Factor Pneumolysin in vitro

“…With respect to a possible antimicrobial effect of so-called 'non-antibiotics', we investigated the influence of a selection of commonly prescribed anti-inflammatory and psychotropic drugs on the production and release of pneumolysin, as these drug families showed some antimicrobial activity [10] . For our in vitro investigations, we chose concentrations near the concentrations reached in human plasma during treatment for other diseases: diclofenac (5 mg/l) [11] , acetyl salicylic acid (50 mg/l) [12] , lithium (1 m M) [13] , amitriptyline (200 g/l) [14] , fluoxetine (200 g/l) [15] , thioridazine (200 g/l) [16] and prednisolone (1 mg/l) [17] . The antibiotics and the other compounds investigated were tested in two separate series of experiments, resulting in two different control groups.…”