Plasma, urine and skin pharmacokinetics of cefepime in burns patients.

We studied the pharmacokinetics of cefepime (2 g bd) in six burns patients. Blood, urine and skin samples were collected to measure cefepime concentrations. A two-compartment model was fitted to the data. At day 1, t(1/2beta) was 2.45 +/- 0.56 h, V(ss) 0.36 +/- 0.1 L/kg, total clearance 152 +/- 25.2 mL/min, and AUC 217 +/- 34 mg*h/L. There was no statistical difference between day 1 and day 3 for any of the pharmacokinetic parameters. We demonstrated good penetration of cefepime in skin. These results show that it is not necessary to change the standard dosage of cefepime in burns patients.

Evidence for a tissue-specific induction of cutaneous CYP2E1 by dexamethasone.

We studied in mouse the effect of topical application of dexamethasone or salicylic acid, on CYP2E1 and CYP3A expression (proteins and/or mRNA) in liver and skin. Dexamethasone was also administered by intraperitoneal injection. Topical application or intraperitoneal injection of dexamethasone increased cutaneous CYP2E1 (8 and 4-fold respectively) whereas the hepatic level of this isoform showed a slight decrease and hepatic CYP3A expression was increased (3-fold). Cutaneous CYP2E1 was increased (3-fold) after topical treatment by salicylic acid. This compound had no effect on hepatic CYP3A and CYP2E1 expression. Cutaneous CYP3A (protein and mRNA) was not detectable in all groups (control or treated animals). Dexamethasone and salicylic acid increased cutaneous CYP2E1 mRNA level (2.5 and 1.4-fold respectively). In conclusion, dexamethasone and salicylic acid induced cutaneous CYP2E1 protein and mRNA level. Cutaneous CYP2E1 induction by dexamethasone is a tissue-specific process.

In vitro metabolism of three major isomers of retinoic acid in rats. Intersex and interstrain comparison.

Cytochrome P450 expression in liver is influenced by several factors, including sex and strain. Whereas little is known about their metabolic capabilities, Hairless rats are widely used for the studies of tropical agents. We compared Sprague-Dawley and Hairless rat metabolic behavior to validate the use of Hairless rats in pharmacokinetic and metabolic studies of topically applied drugs. Liver microsomes of male and female rats of both strains were used to investigate the in vitro metabolism of three retinoic acid (RA) isomers: all-trans-RA, 13-cis-RA, and 9-cis-RA. In all cases, a major isomerization of the tested isomer in the two others was observed. This process was independent of the presence of NADPH, but depended on the presence of microsomal proteins. In addition, we observed, to a lesser extent, the formation of 4-oxo metabolites (4-oxo-all-trans-RA, 4-oxo-13-cis-RA, and 4-oxo-9-cis-RA), with the rate of formation of each of these compounds varying with the nature of the isomer incubated. The 4-oxo metabolites formed were statistically greater in male than in female rats in the two strains studied. No significant difference in RA biotransformation was observed between Sprague-Dawley and Hairless rats. In addition, no major difference was observed between the two strains concerning the expression of the different cytochrome P450 isoforms studied. In conclusion, phase I metabolism of RAs characterized by C4-hydroxylation varied with sex, but not within the two strains studied in rats. These results strengthen the relevance of the use of Hairless rats in pharmacokinetic and metabolic studies of topical agents, including retinoids.

Comparative effects of antifungal agents on zidovudine glucuronidation by human liver microsomes.

Zidovudine (ZDV) is extensively metabolised by the liver to an inactive glucuronide (GZDV). Since ZDV is often administered with antimycotic drugs, we studied the effect of six systemic antifungal agents on the in vitro glucuronidation of ZDV by human liver microsomes. 5-fluorocytosine and itraconazole had no inhibitory effect whereas amphotericine B, ketoconazole, miconazole and fluconazole inhibited in vitro GZDV formation (Ki values were 0.13, 0.08, 0.18 and 1.4 mM respectively).