Pharmacokinetics Of Celecoxib Research Articles

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.

Investigation of the pharmacokinetics of celecoxib by liquid chromatography–mass spectrometry

Investigation of the pharmacokinetics of celecoxib by liquid chromatography–mass spectrometry

Investigation of the pharmacokinetics of celecoxib by liquid chromatography-mass spectrometry.

A new method for the quantification of celecoxib in human plasma based on reversed-phase high-performance liquid chromatography (HPLC) coupled to atmospheric pressure chemical ionization (APCI) mass spectrometry (MS) after liquid-liquid extraction is presented. The method is rapid, sensitive and highly selective. The retention time of celecoxib was 2.3 min. The limit of quantification was 5 microg/L. Rofecoxib was used as internal standard. After validation, the method was used to study the pharmacokinetic profile of celecoxib following administration of a single oral dose (200 mg) in 12 healthy volunteers. Since celecoxib should be metabolized primarily by cytochrome 2C9 (CYP2C9), a poor metabolizer (PM) for this cytochrome P450 enzyme was included in the study. Pharmacokinetic characteristics (mean +/- SD) of extensive metabolizers (EM) were t(max) 2.9+/-1.2h, c(max) 842+/-280 microg/L, AUC(infinity) 6246+/-2147 microg h/L and t(1/2) 7.8+/-2.7h. The area under the curve (AUC(infinity)) for the PM was 12561 microg h/L. However, we found no noticeable increase in half life in the PM (11.5 h) after a single dose of celecoxib.

Determination of celecoxib in human plasma and rat microdialysis samples by liquid chromatography tandem mass spectrometry

Methods for the determination of celecoxib in human plasma and rat microdialysis samples using liquid chromatography tandem mass spectrometry are described. Celecoxib and an internal standard were extracted from plasma by solid-phase extraction with C 18 cartridges. Thereafter compounds were separated on a short narrow bore RP C 18 column (30×2 mm). Microdialysis samples did not require extraction and were injected directly using a narrow bore RP C 18 column (70×2 mm). The detection was by a PE Sciex API 3000 mass spectrometer equipped with a turbo ion spray interface. The compounds were detected in the negative ion mode using the mass transitions m/ z 380→316 and m/ z 366→302 for celecoxib and internal standard, respectively. The assay was validated for human plasma over a concentration range of 0.25–250 ng/ml using 0.2 ml of sample. The assay for microdialysis samples (50 μl) was validated over a concentration range of 0.5–20 ng/ml. The method was utilised to determine pharmacokinetics of celecoxib in human plasma and in rat spinal cord perfusate.

In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics.

In-vitro studies were conducted to assess the impact of CYP2C9 genotype on the metabolism (methyl hydroxylation) and pharmacokinetics of celecoxib, a novel cyclooxygenase-2 inhibitor and CYP2C9 substrate. When compared to cDNA-expressed wild-type CYP2C9 (CYP2C9*1), the Vmax/Km ratio for celecoxib methyl hydroxylation was reduced by 34% and 90% in the presence of recombinant CYP2C9*2 and CYP2C9*3, respectively. These data indicated that the amino acid substitution at position 359 (Ile to Leu) elicited a more pronounced effect on the metabolism of celecoxib than did a substitution at position 144 (Arg to Cys). The Vmax/Km ratio was also decreased in microsomes of livers genotyped CYP2C9*1/*2 (47% decrease, mean of two livers), or CYP2C9*1/*3 (59% decrease, one liver). In all cases, these changes were largely reflective of a decrease in Vmax, with a minimal change in Km. Based on simulations of the in-vitro data obtained with the recombinant CYP2C9 proteins, it was anticipated that the pharmacokinetics of celecoxib (as a much as a five-fold increase in plasma AUC) would be altered (versus CYP2C9*1/*1 subjects) in subjects genotyped heterozygous or homozygous for the CYP2C9*2 (Cys144) or CYP2C9*3 (Leu359) allele. In a subsequent clinical study, the AUC of celecoxib was increased (versus CYP2C9*1/*1 subjects) approximately 2.2-fold (range, 1.6-3-fold) in two CYP2C9*1/*3 subjects and one CYP2C9*3/*3 subject receiving a single oral dose (200 mg) of the drug. In contrast, there was no significant change in celecoxib AUC in two subjects genotyped CYP2C9*1/*2.