Pharmacokinetics Of Diclofenac Research Articles

The pharmacokinetics of diclofenac and its interaction with sulfadoxine-trimethoprim in sheep

ObjectiveIn this study, the pharmacokinetics of diclofenac was determined following a single intravenous and intramuscular administration of diclofenac alone and co-administration with sulfadoxine-trimethoprim in sheep. Study designA randomized, controlled, experimental study. AnimalsA total of 18 healthy male Ivesi sheep were used in the study (2–4 years old, with an average weight of 50 ± 5 kg). MethodsDiclofenac was administered alone in the 1st group intramuscular (1 mg/kg), intravenous (1 mg/kg) in the 2nd group, and together (intramuscular diclofenac (1 mg/kg) and intravenous sulfadoxine -trimethoprim (5 mg/kg)) in the 3rd group. Blood was collected at 2, 5, 10, 15, 30, and 45 min and 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 h following the administration. The plasma concentration of diclofenac was determined with high-performance liquid chromatography (HPLC). Pharmacokinetic parameters were analyzed using a non-compartmental analysis pharmacokinetic model. ResultsThe elimination half-life (t½), area under the plasma concentration-time curve (AUC), mean residence time (MRT), volume of distribution at steady-state (Vd), total body clearance (ClT), and bioavailability (F) values following the diclofenac were evaluated IM alone 2.31 ± 0.01 h, 3.31 ± 0.06 h* µg/mL, 3.52 ± 0.02 h, 0.96 ± 0.02 L/kg, 0.28 ± 0.00 mL/h/kg, 93%, respectively. When co-administered with sulfadoxine-trimethoprim the same kinetic values of diclofenac were 3.62 ± 0.09 h, 3.52 ± 0.05 h* µg/mL, 5.54 ± 0.46 h, 1.45 ± 0.17 L/kg, 0.24 ± 0.00 mL/h/kg and 99%, respectively. Sulfadoxine-trimethoprim increased the t½, AUC, MRT, Vd, and F values of diclofenac at statistically significant levels, and decreased the ClT value. Conclusions and clinical relevanceThe results of the study indicate that the pharmacokinetics of diclofenac are altered when used with sulfadoxine-trimethoprim. Therefore, if the two drugs are used together, a new dose adjustment should be made for diclofenac.

Proteomics‐informed physiologically‐based pharmacokinetic (PBPK) modeling revealed differential effects of UGT2B17 variability on the pharmacokinetics of diclofenac following intravenous and oral administration

Uridine 5′‐diphospho‐glucuronosyltransferase 2B17 (UGT2B17) demonstrates dramatic inter‐individual variability (>3000‐fold) in the activity and expression in humans, which is associated with age, sex, genotype, and ethnicity.1We recently found that diclofenac is a UGT2B17 substrate, however, the quantitative contribution of UGT2B17 in the metabolism and pharmacokinetics (PK) of diclofenac is not well studied. Moreover, we hypothesized that the higher intestinal abundance of UGT2B17 could further amplify the magnitude and variability in its in vivo PK. We first investigated diclofenac glucuronide (DG) formation kinetics in human liver microsomes (HLM) and human intestinal microsomes (HIM) that were isolated from human donors containing the deletion genotype and the highest‐expressor of UGT2B17 in our tissue bank. Diclofenac showed 4‐ and 16‐fold difference in maximum DG formation rate (Vmax) in UGT2B17 highest‐expressor versus deletion in HLM and HIM, respectively (Fig. 1). Proteomics‐informed PBPK modeling2 estimated the quantitative contribution (fm) of UGT2B17 in the intestinal and hepatic glucuronidation of diclofenac, which revealed fm of 0.77, 0.24, and 0.0 in the highest, average, and null UGT2B17 expressors, respectively. Interestingly, intestinal fm of UGT2B17 was 0.94, 0.90, and 0.0 in the highest, average, and null expressors, respectively. The organ‐specific changes in the fm were also substantiated by the predicted fraction gut escaped (fg), which was primarily associated with UGT2B17 abundance in the enterocytes. A PBPK model was first developed and validated in the UGT2B17 average expressor and then extended to other populations utilizing UGT2B17 abundance data. Predicted plasma levels (AUC) of diclofenac were 20 % and 100 % higher following an IV dose (50 mg) in UGT2B17 deletion versus the average and the highest expressor subjects, respectively. Similalry, after 50 mg oral dose, ~2‐fold and 8.5‐fold higher AUC was observed in UGT2B17 deletion as compared to that in the average and the highest UGT2B17 expressors, respectively. Sex differences in UGT2B17 abundance explained ~2‐fold higher diclofenac AUC in females after oral administration. In summary, the unique intestinal abundance and the highly prevalent gene deletion of UGT2B17 could likely contribute to the variable bioavailability of its substrate drugs. Similarly, poor metabolism of diclofenac in children and in UGT2B17 deletion subjects could predispose these patients to high GI discomfort.References Bhatt et al., Drug Metab. Dispos. (2018). Parvez Md M et al., Drug Metab. Dispos.(2021).

Skin pharmacokinetics of diclofenac and co-delivered functional excipients

An important question in the development of a dermatological drug product is whether a target concentration has been achieved in, for example, the viable epidermis following topical administration. When attempting to address this challenge, it is essential to consider the role of excipients in the formulation that may influence drug partitioning and diffusion in the different layers of the skin. The objective, therefore, was to correlate, in human subjects, the skin pharmacokinetics of diclofenac (specifically, its uptake into and clearance from the stratum corneum (SC)) from an approved drug product (Voltaren® medicated plaster) with the in vivo co-uptake of two key excipients, namely propylene glycol and butylene glycol. SC sampling was used to assess diclofenac input into the skin during patch application, and its subsequent clearance post-removal of the delivery system. In parallel the uptake of the two glycol excipients was also measured. Drug and excipient amounts in the SC increased with time of application up to 6 h and, for diclofenac, no further increase was observed when the administration was prolonged to 12 h. When the plaster was removed after 6 h of wear, diclofenac cleared relatively slowly from the SC suggesting that drug binding with a slow off-rate had occurred. The results indicate that the optimisation of drug delivery from a topical formulation must take into account the disposition of key excipients and their impact on dermato-pharmacokinetics in general.

The Pharmacokinetics of Diclofenac and its Interaction with Sulfadoxine-Trimethoprim in Sheep

The Pharmacokinetics of Diclofenac and its Interaction with Sulfadoxine-Trimethoprim in Sheep

Effect of rutin on pharmacokinetic modulation of diclofenac in rats

Diclofenac is an extensively used nonsteroidal anti-inflammatory drug, but gastrointestinal liabilities and cardiovascular complications take the shine away from such a widely prescribed drug. On the other hand, rutin, a dietary bioflavonoid, has quite a few pharmacological attributes to improve the efficacy and reduce the dose-related toxicities of diclofenac through the intended food-drug/herb-drug interaction. The aim of the present research work was to investigate the role of rutin on pharmacokinetic modulation and the consequent efficacy of diclofenac. At first, pharmacodynamics and pharmacokinetics of diclofenac as alone and in the presence of rutin were investigated orally in a rat model. Then, mechanistic studies were performed to explain the effect of rutin on improvement in oral exposure as well as the efficacy of diclofenac using a battery of in-vitro/in-situ/in-vivo studies. Results displayed that rutin enhanced efficacy as well as oral bioavailability of diclofenac in rats. A marked increase in permeability of diclofenac by rutin was displayed that is linked to inhibition of Breast Cancer Resistance Protein (BCRP) transporters. There was no significant effect of rutin on the modulation of intestinal transit, CYP2C9 inhibition in human liver microsomes, and CYP2C9/CYP2C11 expression in rat liver tissues to boost the oral exposure of diclofenac. Rutin is found to be an inhibitor for BCRP transporters and can act as an oral bioavailability enhancer for a drug like diclofenac.

Lack of Correlation between In Vitro and In Vivo Studies on the Inhibitory Effects of (‒)-Sophoranone on CYP2C9 is Attributable to Low Oral Absorption and Extensive Plasma Protein Binding of (‒)-Sophoranone.

(‒)-Sophoranone (SPN) is a bioactive component of Sophora tonkinensis with various pharmacological activities. This study aims to evaluate its in vitro and in vivo inhibitory potential against the nine major CYP enzymes. Of the nine tested CYPs, it exerted the strongest inhibitory effect on CYP2C9-mediated tolbutamide 4-hydroxylation with the lowest IC50 (Ki) value of 0.966 ± 0.149 μM (0.503 ± 0.0383 μM), in a competitive manner. Additionally, it strongly inhibited other CYP2C9-catalyzed diclofenac 4′-hydroxylation and losartan oxidation activities. Upon 30 min pre-incubation of human liver microsomes with SPN in the presence of NADPH, no obvious shift in IC50 was observed, suggesting that SPN is not a time-dependent inactivator of the nine CYPs. However, oral co-administration of SPN had no significant effect on the pharmacokinetics of diclofenac and 4′-hydroxydiclofenac in rats. Overall, SPN is a potent inhibitor of CYP2C9 in vitro but not in vivo. The very low permeability of SPN in Caco-2 cells (Papp value of 0.115 × 10−6 cm/s), which suggests poor absorption in vivo, and its high degree of plasma protein binding (>99.9%) may lead to the lack of in vitro–in vivo correlation. These findings will be helpful for the safe and effective clinical use of SPN.

Different Roles of Human Cytochrome P450 2C9 and 3A Enzymes in Diclofenac 4'- and 5-Hydroxylations Mediated by Metabolically Inactivated Human Hepatocytes in Previously Transplanted Chimeric Mice.

To investigate the respective roles of cytochromes P450 2C9 and 3A in drug oxidation in human livers, the in vivo pharmacokinetics of S-warfarin and diclofenac were analyzed after intravenous administrations in chimeric mice that had been transplanted with human hepatocytes. P450 2C9 was metabolically inactivated in the humanized mice by orally pretreating them with tienilic acid. After intravenous administration of S-warfarin, a significant difference in the concentration-time profiles of the primary metabolite 7-hydroxywarfarin between untreated mice and mice treated with tienilic acid was observed. In contrast, there were no apparent differences in the profiles for S-warfarin between the treated and untreated groups. The mean values of the maximum concentrations (Cmax) and the areas under the plasma concentration versus time curves (AUCinfinity) for 7-hydroxywarfarin were significantly lower (22 and 16% of the untreated values, respectively) in the treated group. This presumably resulted from suppressed P450 2C9 activity in the primary oxidative metabolism in vivo in the treated group. After diclofenac administration, plasma levels of diclofenac, 5-hydroxydiclofenac, and diclofenac acylglucuronide were roughly similar in pretreated and untreated mice. However, the mean Cmax and AUCinfinity values for 4'-hydroxydiclofenac were significantly lower (38 and 53% of the untreated group, respectively) in the treated group. The reported value of ∼0.8 for the fraction of S-warfarin metabolized to 7-hydroxywarfarin mediated by P450 2C9 in in vitro systems was similar to the value implied by the present humanized-liver mouse model pretreated with tienilic acid in which the AUC of 7-hydroxywarfarin was reduced by 84%. In contrast, the fractions of diclofenac metabolized to 4'-hydroxydiclofenac in in vitro and in vivo experiments were inconsistent. These results suggested that humanized-liver mice orally treated with tienilic acid might constitute an in vivo model for metabolically inactivated P450 2C9 in human hepatocytes transplanted into chimeric mice. Moreover, diclofenac, a typical in vitro P450 2C9 probe substrate, was cleared differently in vitro and in humanized-liver mice in vivo.

The pharmacokinetics and metabolism of diclofenac in chimeric humanized and murinized FRG mice.

The pharmacokinetics of diclofenac were investigated following single oral doses of 10mg/kg to chimeric liver humanized and murinized FRG and C57BL/6 mice. In addition, the metabolism and excretion were investigated in chimeric liver humanized and murinized FRG mice. Diclofenac reached maximum blood concentrations of 2.43 ± 0.9µg/mL (n = 3) at 0.25h post-dose with an AUCinf of 3.67µgh/mL and an effective half-life of 0.86h (n = 2). In the murinized animals, maximum blood concentrations were determined as 3.86 ± 2.31µg/mL at 0.25h post-dose with an AUCinf of 4.94 ± 2.93µg h/mL and a half-life of 0.52 ± 0.03h (n = 3). In C57BL/6J mice, mean peak blood concentrations of 2.31 ± 0.53µg/mL were seen 0.25h post-dose with a mean AUCinf of 2.10 ± 0.49µgh/mL and a half-life of 0.51 ± 0.49h (n = 3). Analysis of blood indicated only trace quantities of drug-related material in chimeric humanized and murinized FRG mice. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles in humanized mice were different to those of both murinized and wild-type animals, e.g., a higher proportion of the dose was detected in the form of acyl glucuronide metabolites and much reduced amounts as taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57BL/6J mice and humans revealed a greater, though not complete, match between chimeric humanized mice and humans, such that the liver humanized FRG model may represent a model for assessing the biotransformation of such compounds in humans.

Pharmacokinetics of Diclofenac and Hydroxypropyl‐β‐Cyclodextrin (HPβCD) Following Administration of Injectable HPβCD‐Diclofenac in Subjects With Mild to Moderate Renal Insufficiency or Mild Hepatic Impairment

Given their established analgesic properties, nonsteroidal anti‐inflammatory drugs (NSAIDs) represent an important postoperative pain management option. This study investigated: (1) the effects of mild or moderate renal insufficiency and mild hepatic impairment on the pharmacokinetics (PK) of diclofenac and hydroxypropyl‐β‐cyclodextrin (HPβCD) following administration of the injectable NSAID HPβCD‐diclofenac; and (2) the PK of HPβCD following administration of HPβCD‐diclofenac and intravenous itraconazole formulated with HPβCD in healthy adults. Diclofenac clearance (CL) and volume of distribution (Vz) tended to increase with decreasing renal function (moderate insufficiency versus mild insufficiency or healthy controls). Regression analysis demonstrated a significant relationship between Vz (but not CL or elimination half‐life, t½) and renal function. HPβCD CL was significantly decreased in subjects with renal insufficiency, with a corresponding increase in t½. There were no significant differences in diclofenac or HPβCD PK in subjects with mild hepatic impairment versus healthy subjects. Exposure to HPβCD in healthy subjects following HPβCD‐diclofenac administration was ∼12% of that with intravenous itraconazole, after adjusting for dosing schedule and predicted accumulation (<5% without adjustment). With respect to PK properties, these results suggest that HPβCD‐diclofenac might be administered to patients with mild or moderate renal insufficiency or mild hepatic impairment without dose adjustment (NCT00805090).

Predictive Performance of Physiologically Based Pharmacokinetic (PBPK) Modeling of Drugs Extensively Metabolized by Major Cytochrome P450s in Children.

The accuracy of physiologically based pharmacokinetic (PBPK) model prediction in children, especially those younger than 2 years old, has not been systematically evaluated. The aim of this study was to characterize the pediatric predictive performance of the PBPK approach for 10 drugs extensively metabolized by CYP1A2 (theophylline), CYP2C8 (desloratidine, montelukast), CYP2C9 (diclofenac), CYP2C19 (esomeprazole, lansoprazole), CYP2D6 (tramadol), and CYP3A4 (itraconazole, ondansetron, sufentanil). Model performance in children was evaluated by comparing simulated plasma concentration-time profiles with observed clinical results for each drug and age group. PBPK models reasonably predicted the pharmacokinetics of desloratadine, diclofenac, itraconazole, lansoprazole, montelukast, ondansetron, sufentanil, theophylline, and tramadol across all age groups. Collectively, 58 out of 67 predictions were within 2-fold and 43 out of 67 predictions within 1.5-fold of observed values. Developed PBPK models can reasonably predict exposure in children age 1 month and older for an array of predominantly CYP metabolized drugs.

Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies

Investigation of the pharmacokinetics (PK) of a compound is of significant importance during the early stages of drug development, and therefore several in vitro systems are routinely employed for this purpose. However, the need for more physiologically realistic in vitro models has recently fueled the emerging field of tissue-engineered 3D cultures, also referred to as organs-on-chips, or microphysiological systems (MPSs). We have developed a novel fluidic platform that interconnects multiple MPSs, allowing PK studies in multi-organ in vitro systems along with the collection of high-content quantitative data. This platform was employed here to integrate a gut and a liver MPS together in continuous communication, and investigate simultaneously different PK processes taking place after oral drug administration in humans (e.g., intestinal permeability, hepatic metabolism). Measurement of tissue-specific phenotypic metrics indicated that gut and liver MPSs can be fluidically coupled with circulating common medium without compromising their functionality. The PK of diclofenac and hydrocortisone was investigated under different experimental perturbations, and results illustrate the robustness of this integrated system for quantitative PK studies. Mechanistic model-based analysis of the obtained data allowed the derivation of the intrinsic parameters (e.g., permeability, metabolic clearance) associated with the PK processes taking place in each MPS. Although these processes were not substantially affected by the gut-liver interaction, our results indicate that inter-MPS communication can have a modulating effect (hepatic metabolism upregulation). We envision that our integrative approach, which combines multi-cellular tissue models, multi-MPS platforms, and quantitative mechanistic modeling, will have broad applicability in pre-clinical drug development.

Pharmacokinetics of diclofenac in healthy controls with wild-type phenotype for CYP2C9 shows metabolism variability

BackgroundCytochrome P450 2C9 (CYP2C9) is an important enzyme in the metabolism of many drugs, including NSAIDs, antidepressants and anticoagulants. In vitro and in vivo studies have demonstrated that CYP2C9 polymorphisms modify the activity of the enzyme and subsequently the metabolism of different drugs. ObjectiveTo characterize the diclofenac pharmacokinetics in healthy subjects with the wild type form of CYP2C9 genotype. MethodsTwenty five healthy women were included in the study; a single dose of diclofenac (50mg) was administered orally. Pharmacokinetic analyses at 12 different times were performed. DNA was extracted from peripheral blood and analyzed through direct sequencing. The CYP2C9*1/*1 allele was found in all subjects. Using the AUC 0-inf parameter, we classified the 25 volunteers as poor, intermediate and extensive metabolizer (2285.421/3217.442/4637.450, respectively). We detected statistical significant differences between the groups, especially between poor metabolizers versus intermediate and extensive metabolizers. ConclusionsThis data indicate that CYP2C9 is not the only enzyme responsible of the metabolism of diclofenac, so it is important to analyze other cytochromes and their variants potentially involved in the metabolism of this drug.

Ciprofloxacin blocked enterohepatic circulation of diclofenac and alleviated NSAID-induced enteropathy in rats partly by inhibiting intestinal β-glucuronidase activity.

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID), which may cause serious intestinal adverse reactions (enteropathy). In this study we investigated whether co-administration of ciprofloxacin affected the pharmacokinetics of diclofenac and diclofenac-induced enteropathy in rats. The pharmacokinetics of diclofenac was assessed in rats after receiving diclofenac (10 mg/kg, ig, or 5 mg/kg, iv), with or without ciprofloxacin (20 mg/kg, ig) co-administered. After receiving 6 oral doses or 15 intravenous doses of diclofenac, the rats were sacrificed, and small intestine was removed to examine diclofenac-induced enteropathy. β-Glucuronidase activity in intestinal content, bovine liver and E coli was evaluated. Following oral or intravenous administration, the pharmacokinetic profile of diclofenac displayed typical enterohepatic circulation, and co-administration of ciprofloxacin abolished the enterohepatic circulation, resulted in significant reduction in the plasma content of diclofenac. In control rats, β-glucuronidase activity in small intestinal content was region-dependent: proximal intestine<distal intestine<ileal valve. Administration of ciprofloxac caused significant reduction of β-glucuronidase activity in distal small intestine, and particularly in ileal valve. Furthermore, ciprofloxacin (10-2000 μmol/L) dose-dependently inhibited β-glucuronidase activity in distal small intestine content or E coli incubated in vitro, but did not affect that in proximal small intestine content or bovine liver incubated in vitro. After receiving 6 oral doses or 15 intravenous doses of diclofenac, typical enteropathy was developed with severe enteropathy occurred in distal small intestine. Co-administration of ciprofloxacin significantly alleviated diclofenac-induced enteropathy. Co-administration of ciprofloxacin attenuated enterohepatic circulation of diclofenac and alleviated diclofenac-induced enteropathy in rats, partly via the inhibition of intestinal β-glucuronidase activity.

Study on influence of piperine treatment on the pharmacokinetics of diclofenac in healthy volunteers

1. Diclofenac sodium (DIC) is a widely used anti-inflammatory drug and its administration in humans receiving long-term therapy with herbal drugs containing piperine (PIP) may occur, which leads to drug–phytochemical interactions. The purpose of the present study was to investigate the influence of PIP treatment on the pharmacokinetics of DIC in healthy volunteers.2. The open-label, two period, sequential study was conducted in 12 healthy volunteers. PIP 20 mg was administered once daily for 10 days during treatment phase. A single dose of DIC 100 mg was administered during control and after treatment phases under fasting conditions. The blood samples were collected after DIC dosing at predetermined time intervals and analyzed by HPLC.3. Treatment with PIP significantly enhanced maximum plasma concentration (Cmax) (2.24–3.68 μg/mL, p < 0.05), area under the curve (AUC) (7.09–11.81 μg h/mL, p < 0.05), half-life (T1/2) (1.23–1.65 h, p < 0.05) and significantly decreased elimination rate constant (Kel) (0.62–0.41 h−1, p < 0.05), apparent oral clearance (CL/F) (7.57–4.52 L/h, p < 0.05) of DIC as compared to that of control phase.4. The results suggest that the altered pharmacokinetics of DIC might be attributed to PIP mediated inhibition of CYP2C9 enzyme, which indicates the clinically significant interaction present between DIC and PIP. Therefore, the combination therapy of DIC along with PIP may represent a novel approach to reduce dosage and result in reduced incidence of gastrointestinal side effects seen with DIC alone at higher doses.

Rapid absorption of diclofenac and acetaminophen after their oral administration to cattle.

The oral pharmacokinetics of diclofenac (DF) were evaluated in cattle by analyzing plasma concentration-time data after its intravenous and oral administration in order to propose the oral administration of DF as effective route to avoid long withdraw period. DF was intravenously and orally administered at 1 mg/kg to cattle using a crossover design with a 4-week washout period. Plasma concentrations of DF were determined by a HPLC analysis. The mean absorption time (MAT) and absorption half-life (t1/2ka) were 1.61 ± 0.61 and 1.51 ± 0.38 hr, respectively, and bioavailability was nearly 100%. The oral pharmacokinetics of acetaminophen (AAP) were also evaluated in cattle. Plasma concentrations of AAP were determined by a HPLC analysis. MAT and t1/2ka were 2.85 ± 0.93 and 1.53 ± 0.28 hr, respectively, and bioavailability was approximately 70%. In conclusion, the results of the present study indicate that DF and AAP are rapidly absorbed from the forestomach of cattle. Therefore, the appropriate efficacies of these drugs may be achieved via their oral administration, even in cattle.

Effect of Resveratrol Treatment on the Pharmacokinetics of Diclofenac in Healthy Human Volunteers

The purpose of the present study was to assess the effect of resveratrol (RSV) treatment on the pharmacokinetics of diclofenac (DIC) in healthy human volunteers. The open-label, two period, sequential study was conducted in 12 healthy human volunteers. A single dose of RSV 500 mg was administered daily for 10 days during treatment phase. A single dose of DIC 100 mg was administered during control and after treatment phases under fasting conditions. The blood samples were collected after DIC dosing and analyzed by HPLC. Treatment with RSV significantly enhanced maximum plasma concentration (Cmax) (1.73 to 2.91 µg/mL), area under the curve (AUC) (5.05 to 9.95 g h/mL), half life (T1/2) (1.12 to 1.76 h) and significantly decreased elimination rate constant (Kel ) (0.71 to 0.41 h(-1)), apparent oral clearance (CL/F) (14.58 to 6.48 L/h) of DIC as compared to control. The geometric mean ratios for Cmax, AUC, T1/2, Kel and CL/F of DIC were 1.75, 2.12, 1.65, 0.61 and 0.47, respectively were outside the limits of 0.8-1.25, which indicates clinically significant interaction between DIC and RSV. The results suggest that the altered pharmacokinetics of DIC might be attributed to RSV mediated inhibition of CYP2C9 enzyme. Therefore, combination therapy of DIC along with RSV may represent a novel approach to reduce dosage and results in reduced gastrointestinal side effects of DIC.

Influence of sesamin on CYP2C-mediated diclofenac metabolism: invitro and invivo analysis.

Our previous studies revealed that sesamin caused a mechanism-based inhibition (MBI) of CYP2C9 in human liver microsomes. Additionally, we observed a similar MBI of CYP2C by sesamin in the rat liver microsomes. Sesamin-induced difference spectra of rat or human liver microsomes in the presence of NADPH showed a peak at 459 nm, suggesting the formation of a metabolic–intermediate (MI) complex of cytochrome P450 and the methylenedioxyphenyl group of sesamin. However, the peak disappeared in both liver microsomes within 30 min after the termination of the metabolism. These results suggest that the MI complex of cytochrome P450 and sesamin is unstable, and the effects of sesamin on human CYP2C9- or rat CYP2C-mediated drug metabolism may be small. To confirm this, in vivo studies using rats were performed. The pharmacokinetics of diclofenac, which is mainly metabolized by CYP2C11 in male rats, were investigated after a 3-days administration of sesamin (0, 10, and 100 mg/kg bw). No significant differences were observed among the three groups in the pharmacokinetic parameters, Cmax, Tmax, and AUC. Furthermore, administration of sesamin to rats for 7 days had no significant effects on diclofenac hydroxylation activity in rat liver microsomes. These results demonstrate that no significant interaction occurs between diclofenac and sesamin in rats. Moreover, the results of these in vitro and in vivo studies suggest that no significant interaction may occur between sesamin and diclofenac when sesamin is administered to humans as a supplement, since the standard sesamin dose in humans is much lower than that administered to rats in this study.

Synergistic effect of the interaction between curcumin and diclofenac on the formalin test in rats

The association of non-steroidal anti-inflammatory drugs with certain plant extracts can increase antinociceptive activity, permitting the use of lower doses and thus limiting side effects. Therefore, the aim objective of the current study was to examine the effects of curcumin on the nociception and pharmacokinetics of diclofenac in rats. Antinociception was assessed using the formalin test. Diluted formalin was injected subcutaneously into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60min after injection, and a reduction in formalin-induced flinching was interpreted as an antinociceptive response. Rats were treated with oral diclofenac (1–31mg/kg), curcumin (3.1–100mg/kg) or the diclofenac–curcumin combination (2.4–38.4mg/kg). To determine the possibility of a pharmacokinetic interaction, the oral bioavailability of diclofenac (10mg/kg) was studied in presence and the absence of curcumin (31mg/kg). Diclofenac, curcumin, or diclofenac–curcumin combination produced an antinociceptive effect on the formalin test. ED30 values were estimated for the individual drugs, and an isobologram was constructed. The derived theoretical ED30 for the antinociceptive effect (19.2mg/kg) was significantly different from the observed experimental ED30 value (9.8mg/kg); hence, the interaction between diclofenac and curcumin that mediates the antinociceptive effect was synergistic. Notwithstanding, the interaction does not appear to involve pharmacokinetic mechanisms, as oral curcumin failed to produce any significant alteration in oral diclofenac bioavailability. Data suggest that the diclofenac–curcumin combination can interact at the systemic level and may have therapeutic advantages for the clinical treatment of inflammatory pain.

Phase 1 study assessing dovitinib (TKI258) on the pharmacokinetics of caffeine, diclofenac, omeprazole, and midazolam in patients with advanced solid tumors.

2581 Background: Dovitinib (TKI258) is an oral tyrosine kinase inhibitor targeting kinases involved in tumor cell proliferation and survival, including FGFR, VEGFR, PDGFR, c-KIT, and FLT3. In vitro...

Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

To characterize pharmacokinetic-pharmacodynamic modeling of diclofenac in Freund's complete adjuvant (FCA)-induced arthritic rats using prostaglandin E(2) (PGE(2)) as a biomarker. The pharmacokinetics of diclofenac was investigated using 20-day-old arthritic rats. PGE(2) level in the rats was measured using an enzyme immunoassay. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to illustrate the relationship between the plasma concentration of diclofenac and the inhibition of PGE(2) production. The inhibition of diclofenac on lipopolysaccharide (LPS)-induced PGE(2) production in blood cells was investigated in vitro. Similar pharmacokinetic behavior of diclofenac was found both in normal and FCA-induced arthritic rats. Diclofenac significantly decreased the plasma levels of PGE(2) in both normal and arthritic rats. The inhibitory effect on PGE(2) levels in the plasma was in proportion to the plasma concentration of diclofenac. No delay in the onset of inhibition was observed, suggesting that the effect compartment was located in the central compartment. An inhibitory effect sigmoid I(max) model was selected to characterize the relationship between the plasma concentration of diclofenac and the inhibition of PGE(2) production in vivo. The I(max) model was also used to illustrate the inhibition of diclofenac on LPS-induced PGE(2) production in blood cells in vitro. Arthritis induced by FCA does not alter the pharmacokinetic behaviors of diclofenac in rats, but the pharmacodynamics of diclofenac is slightly affected. A PK-PD model characterizing an inhibitory effect sigmoid I(max) can be used to fit the relationship between the plasma PGE(2) and diclofenac levels in both normal rats and FCA-induced arthritic rats.