This in vitro study was conducted to evaluate propofol glucuronidation and the effect of concomitantly administered drugs in various species. Propofol glucuronidation was studied in microsomal fractions from rat, rabbit, and human livers. Extrahepatic metabolism was investigated using lung and kidney microsomes. The propofol-uridine diphosphate-glucuronosyltransferase (UGT) activity measured in liver microsomes was higher in rabbit than in rat. Among the three tested species, human livers exhibited the highest activity, with only small variability in the three samples studied. Animal kidney, but not lung (animal or human), microsomes were able to glucuronidate propofol, meaning that extrahepatic metabolism of propofol exists, at least in the kidney, in the tested species (rat and rabbit). Since metabolic interactions are potential sources of prolonged drug effect or overdose, we screened the effect of 21 compounds (known substrates of various UGT or potentially coadministered drugs) on the glucuronidation of propofol by human liver microsomes. Inhibitions obtained with chemicals or drugs glucuronidated by either UGT1 or UGT2 families (1-naphtol, 4-hydroxybiphenyl, carvacrol, n-propylgallate, ketoprofen, chloramphenicol, acetylsalicylic acid) indicated that at least two UGT isoforms are involved in propofol glucuronidation. Inhibition was observed with several drugs potentially coadministered during pre-, per, or postoperative periods (e.g., acetylsalicyclic acid, ketoprofen, oxazepam, fentanyl). Although not directly transposable to the in vivo situation, these results indicate that such interactions are theoretically possible.(ABSTRACT TRUNCATED AT 250 WORDS)
The pharmacokinetics of 222 infusions of high-dose methotrexate (MTX) with leucovorin rescue were studied in 22 adults with osteosarcoma. To reduce the variability of plasma concentration, we individualized dose regimens using a Bayesian method to reach a concentration of 10(-3) M MTX at the end of an 8-h infusion. The mean concentration observed at the end of the infusion was 1016 +/- 143 mumol/l. The mean dose delivered was 13.2 +/- 2 g/m2. The clearance was 49.1 +/- 11.7 ml min-1 m-2. The decay of the plasma concentration of MTX after completion of the infusion followed a two-compartment model with a t1/2 alpha of 2.66 +/- 0.82 h and a t1/2 beta of 15.69 +/- 8.63 h. The volume of distribution was 0.32 +/- 0.08 l/kg. As compared with previously published data, the interindividual and intraindividual variations in the concentration at the end of the infusion were reduced, with values of 14% and 5.9%-21%, respectively, being obtained. Severe toxicities were avoided, and there were only 3 hematologic and 8 digestive grade 3 side effects and no grade 4 complication. The t1/2 alpha and the MTX plasma concentrations at 23 and 47 h were correlated with renal toxicity (P < 0.001). However, no correlation was found between the pharmacokinetic parameters and other signs of toxicity. There was no significant difference in pharmacokinetics between the toxic and nontoxic groups. In the same manner, the parameters of the group of patients sensitive to MTX were not statistically significant different from those of the group of nonsensitive patients.
The human liver metabolism of paclitaxel (Taxol), an anticancer drug, leads to three metabolites: 6alpha-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel and 6alpha,3'-p-dihydroxypaclitaxel. The inter-individual variability of paclitaxel metabolism was investigated first in vitro using 22 human liver microsomes. Three metabolites have been detected by HPLC. This preliminary work revealed marked inter-individual differences in paclitaxel metabolism. The amount of major metabolite 6alpha-hydroxypaclitaxel formed varied 16-fold (0.7 to 11.5 nmol/mg/h). We next studied the effect of 29 compounds (antineoplastics, antiemetics, histamine-2 receptor antagonist, antalgics, antifungals, antivirals, psychotropics, antibiotic, corticoid, antiarrhythmic, calcium channel blocker) on paclitaxel metabolism in human liver microsomes. Among the compounds studied, quercetin, antifungal drugs such as ketoconazole and miconazole, and the antineoplastic drug doxorubicin inhibited formation of 6alpha-hydroxypaclitaxel. Dixon plots indicated that quercetin and doxorubicin inhibited 6alpha-hydroxypaclitaxel formation through a competitive mechanism with a Ki of 10.1 microM and 64.8 microM, respectively. The inhibition of this metabolite by ketoconazole was through a noncompetitive mechanism with a Ki of 11.8 microM. Our data thus suggest that special attention should be paid when these drugs are combined in clinical practice.
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