Pharmacokinetics of diclofenac sodium in chronic active hepatitis and alcoholic cirrhosis.

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.

Vancomycin dosing in morbidly obese patients.

OBJECTIVES AND METHODS: Vancomycin hydrochloride dosing requirements in morbidly obese patients with normal renal function were computed to determine the dose of vancomycin necessary to achieve target steady-state peak and trough concentrations and compared with a normal weight population. RESULTS: Morbidly obese patients [total body weight (TBW) 165 kg, ideal body weight (IBW) 63 kg] required 31.2 mg x kg(-1) x d(-1) TBW or 81.9 mg x kg(-1) x d(-1) IBW to achieve the target concentrations. Normal weight patients (TBW 68.6 kg) required 27.8 mg x kg(-1) x d(-1) to achieve the same concentrations. Because of altered kinetic parameters in the morbidly obese patients (obese: t1/2 = 3.3 h, V = 52 L, CL = 197 ml x min(-1); normal: t1/2=7.2 h, V=46 L, CL=77 ml x min(-1), 20 of 24 patients required q8h dosing (1938 mg q8h) compared with q12h dosing (954 mg q12h) in all normal weight patients in order to avoid trough concentrations that were too low for prolonged periods. There was a good correlation between TBW and CL, but only fair correlation between TBW and V. CONCLUSION: Doses required to achieve desired vancomycin concentrations are similar in morbidly obese and normal weight patients when TBW is used as a dosing weight for the obese (approximately 30 mg x kg(-1) x d(-1)). Shorter dosage intervals may be needed when dosing morbidly obese patients so that steady-state trough concentrations remain above 5 microg x ml(-1) in this population. Because of the large amount of variation in required doses, vancomycin serum concentrations should be obtained in morbidly obese patients to ensure that adequate doses are being administered. Dosage requirements for morbidly obese patients with renal dysfunction require further study.

S-methylation of diethyldithiocarbamic acid in rat liver microsomes.

1. Human hepatic thiol methyltransferase (TMT) is a microsomal enzyme known to catalyse the in vitro S-methylation of diethyldithiocarbamic acid (DDC) to form diethyldithiocarbamic acid methyl ester (methyl DDC). In vivo data are needed to investigate further the biotransformation of DDC to methyl DDC. Thus, we have characterized the in vitro conversion of DDC to methyl DDC using rat liver microsomes with the ultimate goal of establishing an animal model. 2. Formation of methyl DDC in rat liver microsomes was confirmed by hplc analysis. 3. Rat liver microsomes catalysed methylation of DDC with low and high Km's of 5 +/- 6 and 260 +/- 80 microM respectively and with corresponding Vmax's of 0.09 +/- 0.05 and 0.59 +/- 0.04 nmol/min/mg protein. 4. Rat liver TMT activity was maximally inhibited by 57 +/- 6% by 1000 microM 2,3-dichloro-alpha-methylbenzylamine (DCMB), whereas human TMT was completely inhibited. The concentration of half maximal inhibition of rat TMT for DCMB was 2 microM. 5. Incomplete inhibition of rat TMT activity by DCMB suggests a possible alternative pathway of methylation.