Pharmacokinetic and the effect of capsaicin in Capsicum frutescens on decreasing plasma glucose level.

BACKGROUND: The active substance found in Capsicum frutescens (capsicum) that gives hot and spicy flavor is capsaicin, and it seems to have many pharmacological effects. OBJECTIVE: The present research was conducted to study the effect of capsicum on plasma glucose level and to correlate its action with the pharmacokinetic properties of capsaicin in capsicum. MATERIAL AND METHOD: The crossover study was performed in 12 healthy volunteers by performing the OGTT while receiving placebo or 5 grams of capsicum. The insulin secretion and capsaicin level in plasma were measured using the HPLC method. RESULTS: The results of the OGTT showed that plasma glucose levels in volunteers who received capsicum were significantly lower than those in the placebo group at 30 and 45 minutes (p < 0.05). Furthermore, plasma insulin levels were significantly higher at 60, 75, 105, and 120 minutes (p < 0.05). When comparing before and after capsicum intake, the results showed the insulin levels were maintained The pharmacokinetic parameters of capsaicin shown as C(max), T(max), AUC(0-t), T1/2 are 2.47 +/- 0.13 ng/ml, 47.08 +/- 1.99 min, 103.6 +/- 11.3 ng x min/ml, and 24.87 +/- 4.97 min, respectively. CONCLUSION: In conclusion, the present study found that 5 grams of capsicum presented capsaicin levels that were associated with a decrease in plasma glucose levels and the maintenance of insulin levels. The present result might have clinical implications in the management of type 2 diabetes.

Hepatic cytochrome P450 2E1 activity in nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a worldwide phenomenon spanning all the continents. The pathogenesis of NAFLD has not been completely elucidated. One hypothesis is that hepatic cytochrome P450 2E1 (CYP2E1) plays an important role in increasing the lipid peroxidation and oxidative stress in NAFLD. OBJECTIVE: The aim of the present study was to examine hepatic CYP2E1 activity in patients with NAFLD. MATERIAL AND METHOD: Healthy subjects were included. After an overnight fasting, the subjects were orally administered 400 mg chlorzoxazone (CHZ) and serial blood samples were collected at 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6 and 8 hours after dosing. For patients with NAFLD, plasma samples were collected at 0 (predose), 1.5, 2, 2.5 and 3 hours after dosing. Plasma CHZ and 6-hydroxychlorzoxazone (6-OH-CHZ) was assayed by reversed-phase high-performance liquid chromatography (HPLC) with UV detector. Hepatic CYP2E1 activity was calculated by using concentration ratio of 6-OH-CHZ / CHZ. RESULTS: High concentration levels of CHZ and 6-OH-CHZ in healthy subjects were found between 1.5 to 3 hours after the dose. At 1.5 to 3 hours, the concentration ratio of 6-OH-CHZ / CHZ of patients with NAFLD seemed to be more than of healthy subjects. The time point which showed most different was 2.5 hours. (0.40 +/- 0.27 vs. 0.25 +/- 0.12 microg/ml, respectively, p = 0.10). CONCLUSION: Although significant difference of the concentration ratio of 6-OH-CHZ / CHZ between the two groups was not exhibited, the data demonstrated the possibility of the increasing hepatic CYP2E1 activity in NAFLD. The concentration ratio of 6-OH-CHZ / CHZ at the point 2.5 hours may be the best index for measuring hepatic CYP2E1 activity in NAFLD.

A study on the pharmacokinetics of chlorzoxazone in healthy Thai volunteers.

BACKGROUND: Chlorzoxazone (CHZ), a centrally acting skeletal muscle relaxant, is metabolized to 6-hydroxychlorzoxazone (6-OH-CHZ) by CYP2E1. CHZ can be used as an in vivo probe of CYP2E1 activity in patients with liver diseases. Pharmacokinetics of CHZ in Thai subjects should be studied for application to Thai patients. OBJECTIVE: The purpose of the present study was to determine clinical pharmacokinetics of CHZ and 6-OH-CHZ. MATERIAL AND METHOD: Ten healthy Thai volunteers were included. After an overnight fasting, the volunteers were orally administered 400 mg CHZ and serial blood samples were collected at 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, and 8 hours after dosing. Plasma CHZ and 6-OH-CHZ were assayed by reversed-phase high-performance liquid chromatography (HPLC) with UV detector. The pharmacokinetic parameters including maximum concentration (Cmax), time to reach maximum concentration (Tmax), area under the concentration-time curve (AUC0-8 and AUC0-infinity), elimination half-life (t1/2), elimination rate constant (K(el)), oral clearance (Cl), and volume of distribution (Vd) were determined. RESULTS: CHZ was absorbed into systemic circulation with time to reach maximum concentration (Tmax) of 2.00 +/- 0.82 hrs and maximum concentration (Cmax) of 7.15 +/- 2.09 microg/ml. It was metabolized to 6-OH-CHZ with Tmax of 3.05 +/- 1.17 hrs and Cmax of 1.77 +/- 0.50 microg/ml. The extent of CHZ absorption (area under the concentration-time curve, AUC) was 25.47 +/- 7.11 and 27.52 +/- 8.05 microg x hr/ml for AUC0-8 and AUC0-infinity respectively. The AUC0-8 and AUC0-infinity of 6-OH-CHZ were 7.32 +/- 2.21 and 8.50 +/- 2.78 microg x hr/ml, respectively. The elimination rate constant (K(el)) was 0.48 +/- 0.10 and 0.40 +/- 0.13 hr-1 for CHZ and 6-OH-CHZ, respectively The elimination half-life (t1/2) was 1.49 +/- 0.32 and 1.95 +/- 0.73 hours for CHZ and 6-OH-CHZ, respectively. Oral clearance (Cl) and volume of distribution (Vd) of CHZ was found to be 15.77 +/- 4.81 (L/hr) and 33.13 +/- 9.75 L, respectively. CONCLUSION: An oral dose of 400 mg CHZ was used to probe for the pharmacokinetic characteristics of this drug in Thai volunteers. Those parameters reflected absorption, distribution, and elimination of CHZ in healthy Thai volunteers.

The pharmacokinetics of pioglitazone in Thai healthy subjects.

BACKGROUND: Pioglitazone is a thiazolidinedione compound used in the treatment of type 2 diabetes, metabolized mainly by CYP2C8 and CYP3A4. Due to genetic polymorphisms in CYP2C8, interethnic variability in pharmacokinetics should be considered. OBJECTIVE: To conduct a study on the pharmacokinetics of pioglitazone in Thai subjects. MATERIAL AND METHOD: The present study was performed in 24 Thai male healthy subjects. After an overnight fasting, each subject had a single oral dose of 30 mg pioglitazone tablet. Serial blood samples were collected before and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 9, 12, 24 and 48 hours after drug administration. Plasma pioglitazone was determined by automated High Performance Liquid Chromatography (HPLC) with UV detection after deproteinized with acetonitrile. The relevant pharmacokinetic parameters including peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), elimination rate constant (Kel), elimination half-life (T1/2), area under the plasma concentration-time curve (AUC(0-t), AUC(0-inf)), clearance (Cl) and volume of distribution (Vd) were determined. RESULTS: After a single oral dose of 30 mg pioglitazone tablet, the drug was absorbed into systemic circulation with time to maximum concentration (Tmax) at 2.00 +/- 1.61 (0.5-6) hr, and the plasma level reached the maximum concentration (Cmax) of 1.14 +/- 0.29 (0.47-1.63) microg/ml. The AUC was 11.47 +/- 4.77 and 16.69 +/- 7.75 microg x hr/ml for AUC(0-t) and AUC(0-inf) respectively. The elimination rate constant (Kel) of pioglitazone obtained was 0.08 +/- 0.04 hr(-1), whereas the t1/2 was 11.19 +/- 7.38 hrs with the clearance (Cl) of 2.26 +/- 1.22 L/hr. The apparent volume of distribution (Vd) was found to be 30.19 +/- 13.06 L. CONCLUSION: Pharmacokinetic parameters of 30 mg single oral dose of pioglitazone were characterized in Thai subjects. These parameters showed that pioglitazone had a rapid rate of absorption, small volume of distribution and short elimination half-life.

Clinical pharmacokinetic of celecoxib in healthy Thai volunteers.

BACKGROUND: Celecoxib, a nonsteroidal antiinflammatory drug exhibits its antiinflammatory effect by selective inhibition of cyclooxygenase-2 (COX-2) enzyme. Its efficacy has been accepted for the treatment of arthritic pain with superior gastrointestinal side effect profile compared with other conventional NSAIDs. OBJECTIVE: To elucidate clinical pharmacokinetic of celecoxib following an oral dose administration. MATERIAL AND METHOD: Eighteen healthy Thai male volunteers were enrolled in the present study. Their mean age was 20.94 +/- 1.21 years and their mean weight was 63 +/- 5.17 kg. They were orally administered 200 mg celecoxib after an over night fasting, serial blood samples were drawn before and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 and 48 hours after dosing. Plasma celecoxib was analysed by reversed-phase HPLC. RESULTS: Following a 200 mg celecoxib oral administration, the drug was absorbed into the systemic circulation and reach maximum concentration (Tmax) within 2.50 +/- 1.22 hrs by average with the mean peak concentration (Cmax) of 686.83 +/- 211.35 ng/ml. The extent of absorption (area under the curve, AUC) was approximately 5157.12 +/- 1499.46 and 5911.48 +/- 1363.51 ng hr/ml for AUC(0-->t) and AUC(0-->infinity) respectively. The apparent volume of distribution (Vd) was found to be 458.93 +/- 323.28 L/hr. Celecoxib was eliminated after biotransformation and the metabolites were excreted in both urine and feces. The elimination half-life (t(1/2)) of celecoxib appeared to be 8.79 +/- 5.49 hrs with the apparent clearance (CL) of 35.91 +/- 9.85 L. The elimination rate constant for celecoxib obtained from this present study was about 0.11 +/- 0.05 hr(-1). CONCLUSION: Pharmacokinetic parameters following an oral dose of 200 mg celecoxib administration were characterized, including Cmax, Tmax, Vd, kel, CL, AUC. These parameters reflected absorption, distribution, biotransformation and excretion of celecoxib in healthy Thai volunteers.

Detection of polycyclic aromatic hydrocarbon exposure from automobile exhaust fumes using urinary 1-hydroxypyrene level as an index.

Polycyclic aromatic hydrocarbons (PAHs) are hydrocarbon compounds which originate from incomplete combustion. In humans, PAHs are bioactivated to reactive metabolites which can bind covalently to DNA and subsequently initiate mutation and carcinogenesis. The measurement of PAHs exposure may be used as an index to classify a cancer risk group. The purpose of the present study was to measure the level of urinary 1-hydroxypyrene, a metabolite of PAHs, in subjects exposed to automobile exhaust fumes compared to non-exposed subjects. A urine sample was collected from each individual subject after the end of a working day and quantitated for 1-hydroxypyrene and creatinine by HPLC and spectrophotometric method, respectively. The results showed that average urinary 1-hydroxypyrene level in exposed subjects was significantly higher than non-exposed subjects (mean +/- SD of 0.0035 +/- 0.0032 and 0.0011 +/- 0.0010 micromol/l, respectively; P = 0.000). Average urinary creatinine level in exposed subjects was also significantly higher than non-exposed subjects (mean +/- SD of 0.01 +/- 0.005 and 0.008 +/- 0.006 mol/l, respectively; P = 0.040). The ratio of urinary 1-hydroxypyrene/mol creatinine level, of the exposed subjects was significantly higher than that of the non-exposed subjects (mean +/- SD of 0.37 +/- 0.28 and 0.19 +/- 0.22 micromol/mol creatinine, respectively; P = 0.002). CONCLUSION: Automobile exhaust fume exposed subjects have a higher risk to be exposed to PAHs than the non-exposed subjects. Urinary 1-hydroxypyrene level can be used as an index for an exposure of PAHs which have originated from automobile exhaust fumes and other sources as well.

Paraxanthine/caffeine ratio: as an index for CYP1A2 activity in polycyclic aromatic hydrocarbons exposed subjects.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment and originate from incomplete combustion process of organic materials. These compounds are bioactivated to reactive metabolites which bind covalently to DNA and subsequently initiate carcinogenesis. PAHs have been well established as an enzyme inducer of cytochrome P450 (CYP) such as CYP1A1 and CYP1A2. Caffeine is primarily metabolized by CYP1A2 to paraxanthine, so it has been used as a specific probe for assessing CYP1A2 activity. The purpose of this study was to compare CYP1A2 activity in female subjects that were automobile exhaust exposed and non-automobile exhaust exposed using serum paraxanthine/caffeine ratio as an index. Each subject took a 180 mg single oral dose of caffeine solution. Blood samples were collected before and 5 hours after caffeine intake. Serum samples were separated by centrifugation and stored at -20 degrees C until analysis by high performance liquid chromatography (HPLC). Carbon monoxide (CO) level in blood was also detected using spectrophotometer. The results showed that serum paraxanthine/caffeine ratio in exposed subjects was significantly higher than non-exposed subjects (mean +/- SE of 0.45 +/- 0.05 and 0.33 +/- 0.03, respectively; p < 0.05). CO level in exposed subjects was also significantly higher than non-exposed subjects (mean +/- SE of 4.03 +/- 0.21 and 3.01 +/- 0.18, respectively; p < 0.05). Conclusion: Paraxanthine/caffeine ratio, as an index for CYP1A2 activity, can be used to determine PAHs exposure. Automobile exhaust exposed subjects demonstrated significantly higher CYP1A2 activity than that of the non-exposed subjects. Exposed subjects have a possibly higher risk of chemical carcinogenesis.

Caffeine clearance in patients with hepatocellular carcinoma after transcatheter oily chemoembolization treatment.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common neoplasm worldwide, particularly in Asia, with a grave prognosis. Transcatheter Oily Chemoembolization (TOCE) is now universally accepted as the method of choice for the treatment of inoperable HCC. The purpose ofthis study was to evaluate caffeine clearance, a quantitative liver function assessment, in HCC patients before and after treatment with TOCE. METHOD: Both conventional liver function test (LFT) and caffeine clearance were evaluated in twelve patients. Each patient took a 3.5 mg/kg single oral dose of caffeine solution before TOCE, 1 day and 5 weeks after treatment. Blood samples were subsequently collected at 0.5, 1.5, 3, 5, 10 and 24 hours after each dose of caffeine administration and assayed for serum caffeine level by the HPLC technique. Clearance (Cl) was calculated using the equation of Cl = Kel x Vd (Kel = elimination rate constant, Vd = volume of distribution) and half-life was determined using pharmacokinetic analysis. RESULTS: The mean caffeine clearance 1 day after TOCE (0.51 +/- 0.096) and 5 weeks after TOCE treatment (0.43 +/- 0.07) was significantly reduced compared with the mean caffeine clearance before treatment (0.79 . 0.2 ml/min x kg) with the p = 0.06 and p = 0.03, respectively. No significant changes (p > 0.05) in most conventional LFT were observed 5 weeks after treatment. CONCLUSIONS: In the present study, the authors found that caffeine clearance was reduced after TOCE in patients with HCC inspite of no changes in conventional LFT. Thus, the determination of caffeine clearance can serve as a useful parameter for the assessment of hepatic functional reserve in HCC patients post TOCE treatment.

Effects of managerial intervention on drug utilization pattern at King Chulalongkorn Memorial Hospital.

The economic crisis in Thailand since 1997 has a major impact on all sections of the country including health care. There were several suggestions for reducing the drug expenditure budget including restriction of hospital formulary, generic prescribing and generic dispensing. At King Chulalongkorn Memorial hospital, the new hospital formulary was established and implemented in March 1998. The generic dispensing policy was also in place at the same time. This study aimed to evaluate the impact of the new implementation by comparing the prescription patterns in out patient departments (OPDs) of the hospital before and after the new hospital formulary implementation. The prescriptions from several OPDs were systematically stratified samplings 5 weeks before and 5 weeks after March 1st, 1998. The information from the prescriptions including drug category, drug name, amount of dispensed drug, drug cost, etc. was collected and analyzed. The total number of prescriptions and the average number of drug items/prescription before and after the implementation were similar (2,049 vs 2,052, and 2.52 +/- 0.048 vs 2.45 +/- 0.03 respectively). The total cost of the prescription, the cost/prescription and the cost/item seemed to be different (1,690,484 baht vs 1,282,343 baht, 844 +/- 54.04 vs 633 +/- 41.11 and 332.58 +/- 29.59 vs 255.29 +/- 19.98 respectively). After the implementation, physicians in the hospital increasingly prescribed drugs by generic name (37.1% vs 44.85%). Locally made drugs were also prescribed by physicians and received by patients more than before (9.56% vs 84.27% and 28.15% vs 60.72%, respectively). Anti-infective agents were studied in depth as they contribute to significant amount of drug expenditure. The total cost of prescribed anti-infective agents and the cost/prescription were increased after the implementation (223,529 vs 274,435 Baht and 585.38 +/- 102.84 vs 772.71 +/- 147.59). The increased cost mainly came from the cost of anti-HIV drugs. Our data indicate that the new hospital formulary may have played a part on the impact of drug expenditure reduction and may have changed the prescribing attitude of physicians in King Chulalongkorn Memorial Hospital.