No abstract

A clinical study was undertaken in 12 healthy volunteers. At first, subjects received metronidazole (CAS 443-48-1; a substrate for cytochrome CYP3A4 and CYP2C9) alone at a dose of 400 mg every 8 h for 3 days. On day 4, blood and urine were collected at different time points and metronidazole levels were measured. After a washout period (> 10 half-lives) of one week silymarin (CAS 22888-70-6) was given at a daily dose of 140 mg for 9 days. From day 7 both silymarin (140 mg/day) and metronidazole (3 x 400 mg/day) were given till the 9th day. On day 10, blood and urine were collected as above and the levels of metronidazole and its metabolite were measured by HPLC. Administration of silymarin increased the clearence of metronidazole and its major metabolite, hydroxy-metronidazole (HM) by 29.51% and 31.90%, respectively, with a concomitant decrease in half-life, Cmax and AUC(0-48). Urinary excretions of acid-metronidazole (AM), HM as well as metronidazole in 48 h were decreased. The results indicate that silymarin might induce both intestinal P-glycoprotein and CYP3A4 upon multiple dose administration.

A high performance liquid chromatographic (HPLC) method for the simultaneous determination of phenytoin (CAS 57-41-0), phenobarbital (CAS 50-06-6, phenobarbitone) and carbamazepine (CAS 298-46-4) is described. The serum was extracted with ethyl acetate, the dried extract was reconstituted in mobile phase and the aliquot was injected. The eluent drugs were detected at 230 nm. The mobile phase consisting of methanol: water: glacial acetic acid mixture (67:33:1, v/v/v) was used at a flow rate of 1 ml/min on C-18 column. The absolute recovery was above 96% of all the three drugs over a concentration range of 0.5-50.0 micrograms/ml. The inter-day and intra-day precision relative standard deviation (RSD) ranged from 0.79-5.13% and 0.11-6.81%, respectively. The method is simple, rapid, accurate and sensitive and is presently used for therapeutic drug monitoring in epileptic patients. The results obtained with this method showed very good clinical correlation.

Diosmin pretreatment significantly altered the metabolism of metronidazole, as demonstrated by changes in plasma pharmacokinetics as well as by urinary recovery of both parent drug and its major metabolites. This may be caused by the inhibition of cytochrome P(450) enzymes.

DPPH (alpha,alpha-diphenyl-beta-picryl hydrazyl) (CAS 217-591-8), a stable free radical can be used to determine the antioxidant activity (AOA) of some drugs. In the present study the DPPH method was used for the first time to test AOA of dapsone (CAS 80-08-0), clofazimine (CAS 2030-63-9) and rifampicin (CAS 13282-42-1) in vitro and deproteinated blood method. Ascorbic acid (CAS 50-81-7) was used as a control in the study, which showed concentration-dependent antioxidant activity. Rifampicin showed a per se effect but it showed concentration dependent decrease in the DPPH absorbance. Ascorbic acid, dapsone and rifampicin showed DPPH scavenging activity both in vitro and deproteinated blood method. Clofazimine did not have any influence on DPPH. This method may be extended to different drugs for testing their AOA in biological fluids.