Influence of rifampicin pretreatment on the pharmacokinetics of celecoxib in healthy male volunteers.

The effect of rifampicin pretreatment on the pharmacokinetics of celecoxib was investigated in 12 healthy male human volunteers. After an overnight fast, celecoxib 200 mg was administered to the volunteers, either alone or after 5 days pretreatment with once daily dose of 600 mg rifampicin. Serum concentrations of celecoxib were estimated by reverse phase HPLC. Pharmacokinetic parameters were determined based on non-compartmental model analysis using the computer program KINETICA. A significant difference was observed in AUC(0-1) (4531.28 +/- 2147 vs 1629.1 +/- 1006 ng x h x ml(-1), p < 0.0001), AUC(0-infinity) (4632.42 +/- 2221.75 vs 1629.46 +/- 1012.61 ng x h x ml(-1), p = 0.0006), Cmax (544.89 +/- 273.91 vs 238.61 +/- 146.34 ng/ml, p = 0.04), t(1/2) (9.3 +/- 3.58 vs 4.0 +/- 1.43 h, p = 0.0317) and Cl/f (43.14 +/- 36.23 vs 122.85 +/- 95 l x h(-1), p < 0.0001) of celecoxib administered before and after rifampicin pretreatment. However, time to reach peak concentration, tmax (4 +/- 0.88 vs 4 +/- 0.83 h) and volume of distribution Vd/f (583 +/- 251 vs 710 +/- 690 l/kg) were not affected significantly. Rifampicin pretreatment reduced the AUC of celecoxib by 64% and increased the clearance by 185%. This may be due to increased metabolism of celecoxib due to the induction of cytochrome P4502C9 (CYP2C9) in liver. This interaction has a significant clinical relevance and may warrant dosage adjustment when celecoxib is co-administered with rifampicin in chronic treatment conditions, such as tuberculosis, leprosy and other infections of joints, bones, etc.

Validated HPLC method for the determination of celecoxib in human serum and its application in a clinical pharmacokinetic study.

A simple high performance liquid chromatographic method using UV detection for the determination of celecoxib, a specific COX 2 inhibitor, in serum was developed. Serum samples containing the internal standard, tolbutamide, are eluted through a C18, Wakosil column. After extracting with dichloromethane, the eluent is monitored at 250 nm. The mobile phase comprised of 10 mM potassium dihydrogen ortho phosphate (pH 3.2) and acetonitrile (50:50 v/v) with a flow rate of 1 ml/min. Retention times of celecoxib and tolbutamide were 9.6 and 3.5 min, respectively. The mean absolute recovery value was about 70-80%, while the intra day and inter day coefficient of variation and percent error values of the assay method were less than 10%. The calibration curve was linear over a concentration range of 10-1000 ng/ml.

Validated HPLC method for the determination of tinidazole in human serum and its application in a clinical pharmacokinetic study.

A high performance liquid chromatographic (HPLC) method for the determination of tinidazole in human serum using metronidazole as internal standard (IS) is described. Protein precipitation is used for the preparation of sample. Mobile phase consisting of 0.002 M phosphate buffer, methanol and acetonitrile mixture (85:7.5:7.5/v/v/v) was used at a flow rate of 1 ml/min on a C18 column. The eluate was monitored using an UV/Vis detector set at 320 nm. Ratio of peak area of analyte to IS was used for quantification of serum samples. The absolute recovery was greater than 95% over a concentration range of 0.5 to 30 micrograms/ml and the limit of quantitation was 0.05 microgram/ml. The intra-day relative standard deviation (RSD) measured at 0.5, 5, 15 and 30 micrograms/ml ranged from 0.36 to 6.14%. The inter-day RSD ranged from 1.14 to 4.21%. The method is simple, sensitive and has been successfully used in a pharmacokinetic study conducted in healthy human volunteers.

Effect of cephalexin on the pharmacokinetics of metformin in healthy human volunteers.

The purpose of this study was to assess the effect of a single dose of cephalexin on the pharmacokinetics of metformin in healthy human volunteers. A 2 x 2 double blind randomized crossover study was conducted in 12 healthy human volunteers. Each subject received orally either 500 mg of metformin with a placebo or a combination of 500 mg of metformin and 500 mg of cephalexin. Serum and urine levels of metformin were estimated by a validated HPLC method. The systemic disposition of metformin was altered by the co-administration of cephalexin. Cephalexin increased Cmax and AUC by an average of 34% and 24%, respectively, and reduced renal clearance to 14%. The renal clearance of metformin was reduced in a time-dependent manner in the presence of cephalexin. Hence, it is concluded that cephalexin inhibits the renal tubular secretion of metformin resulting in higher circulating serum concentrations.

Formulation and evaluation of diclofenac sodium using hydrophilic matrices.

Controlled-release tablets (having near zero-order release) of diclofenac sodium, a water-soluble drug, were prepared using hydrophilic polymers like hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC), and Carbopol 934. Tablets were also prepared with mixtures of polymers of NaCMC, HPMC, and Carbopol 934. The optimum ratio of drug: HPMC. NaCMC was found to be 1:2:1. A combination of nonionic polymer HPMC and anionic NaCMC polymer matrix resulted in near zero-order release of diclofenac sodium. The results obtained were in agreement with the earlier reports. It is observed that increasing polymer content produces more sustained effect. A combination of nonionic polymer HPMC and anionic polymer NaCMC as the polymer matrix resulted in near zero-order release of diclofenac sodium. Drug release from the matrix did not follow Fick's law of 'diffusion and exhibited near zero-order release. Results of the bioavailability studies indicated that formulation 4 with drug:HPMC:NaCMC equal to 1:2:1 was similar to the marketed product Dicloran SR and showed better bioavailability than Voveran SR. A statistically significant difference was seen between Voveran SR and the other two products. A good in vitro-in vivo correlation was observed for these products.

Effect of clarithromycin on the pharmacokinetics of tolbutamide.

The aim of this 2 x 2 randomized double blind crossover study was to evaluate the effect of a single dose of clarithromycin on the pharmacokinetics of tolbutamide in nine healthy male volunteers. Each volunteer received orally 500 mg of tolbutamide, or 500 mg of tolbutamide and 250 mg of clarithromycin. The washout period between the two treatments was 7 days. Serum levels of tolbutamide were determined by HPLC. Serum profiles were analysed using a non-compartmental model. Blood glucose levels were also estimated using a glucometer (Ames) and Glucostix (Bayer). There was approximately 20% increase in mean absorption rate constant and 26% increase in mean bioavailability of tolbutamide in the presence of clarithromycin. A hypoglycemic effect was reported upon co-administration of the two drugs.