Racial Disparity in Drug Disposition in the Digestive Tract.

The major determinants of drug or, al bioavailability are absorption and metabolism in the digestive tract. Genetic variations can cause significant differences in transporter and enzyme protein expression and function. The racial distribution of selected efflux transporter (i.e., Pgp, BCRP, MRP2) and metabolism enzyme (i.e., UGT1A1, UGT1A8) single nucleotide polymorphisms (SNPs) that are highly expressed in the digestive tract are reviewed in this paper with emphasis on the allele frequency and the impact on drug absorption, metabolism, and in vivo drug exposure. Additionally, preclinical and clinical models used to study the impact of transporter/enzyme SNPs on protein expression and function are also reviewed. The results showed that allele frequency of the major drug efflux transporters and the major intestinal metabolic enzymes are highly different in different races, leading to different drug disposition and exposure. The conclusion is that genetic polymorphism is frequently observed in different races and the related protein expression and drug absorption/metabolism function and drug in vivo exposure can be significantly affected, resulting in variations in drug response. Basic research on race-dependent drug absorption/metabolism is expected, and FDA regulations of drug dosing adjustment based on racial disparity are suggested.

Determination of inositol hexanicotinate in rat plasma by high performance liquid chromatography with UV detection.

A HPLC method with UV detection at 262nm was developed to analyze inositol hexanicotinate in rat plasma. Plasma samples were extracted with an equal volume of acetonitrile, followed by dilution with mobile phase buffer (5mM phosphate buffer, pH 6.0) to eliminate any solvent effects. Inositol hexanicotinate and the internal standard (mebendazole) were separated isocratically using a mobile phase of acetonitrile/phosphate buffer (35:65, v/v, pH 6.0) at a flow rate of 1.0mL/min and a reverse-phase XTerra MS C(18) column (4.6mmx150mm, 3.5microm). The standard curve was linear over a concentration range of 1.5-100.0microg/mL of inositol hexanicotinate in rat plasma. The HPLC method was validated with intra- and inter-day precisions of 1.55-4.30% and 2.69-21.5%, respectively. The intra- and inter-day biases were -0.75 to 19.8% and 2.58-22.0%, respectively. At plasma concentrations of 1.5-100microg/mL, the mean recovery of inositol hexanicotinate was 99.6%. The results of a stability study indicated that inositol hexanicotinate was unstable in rat plasma samples, but was stable in acetonitrile extracts of rat plasma for up to 24h at 4 degrees C. The assay is simple, rapid, specific, sensitive, and reproducible and has been used successfully to analyze inositol hexanicotinate plasma concentrations in a pharmacokinetic study using the rat as an animal model.

Lack of pharmacokinetic interaction between St. John's wort and prednisone.

BACKGROUND: St. John's wort (SJW) is a popular dietary supplement involved in numerous dietary supplement-drug interactions with prescription and non-prescription drugs. The supplement has been shown to affect the metabolism of various CYP3A4 substrates. The CYP3A4 pathway mediates the metabolism of a large number of drug entities, including the corticosteroids prednisone and prednisolone. OBJECTIVE: To examine the effects of long-term SJW administration on the pharmacokinetics of prednisone and its reversible metabolite prednisolone in male subjects. METHODS: Eight male subjects participated in this single-dose study. The pharmacokinetics of prednisone and prednisolone were evaluated before and after 28 days of SJW administration. Plasma corticosteroid concentrations were determined using a normal phase high-performance liquid chromatography assay. Model-independent methods were used to evaluate corticosteroid pharmacokinetics. RESULTS: Twenty-eight days of SJW treatment resulted in no significant alterations in the pharmacokinetic parameters for prednisone or prednisolone. Oral administration of prednisone resulted in prednisone mean +/- SD area under the curves (AUCs) of 115.89 +/- 39.52 microg x h/L prior to SJW treatment and 128.76 +/- 32.71 microg x h/L after 28 days of treatment. Prednisolone mean AUCs were 714.19 +/- 153.29 microg x h/L before SJW administration and 700.74 +/- 89.68 microg x h/L after treatment. CONCLUSIONS: Concurrent administration of SJW had no significant effect on the single-dose pharmacokinetics of prednisone or metabolic prednisolone in male subjects.

Effects of St. John's wort supplementation on ibuprofen pharmacokinetics.

BACKGROUND: St. John's wort is a popular herbal supplement that has been involved in various herb-drug interactions. Experimental findings suggest that the supplement may impact CYP2C9 metabolism. CYP2C9 is responsible for the irreversible metabolism of ibuprofen. OBJECTIVE: To examine the effect of 3 weeks of St. John's wort administration on the stereoselective pharmacokinetics of ibuprofen. METHODS: Eight male subjects participated in this study. The single-dose pharmacokinetics of ibuprofen were evaluated before and after 21 days of St. John's wort administration. Plasma ibuprofen concentrations were determined, using a stereoselective, reversed-phase HPLC assay. Model independent methods were used to evaluate the pharmacokinetics of each ibuprofen enantiomer. Data were analyzed by 2 way ANOVA testing and confidence interval testing. RESULTS: S(+)-ibuprofen mean +/- SD AUC and maximum concentration (C(max)) values were 131.6 +/- 26.8 microg x h/mL and 31.8 +/- 7.33 microg/mL, respectively, for control samples and 122.4 +/- 32.9 microg x h/mL and 33.6 +/- 7.83 microg/mL, respectively, after St. John's wort treatment. R(-)-ibuprofen mean AUC and C(max) values were 85.1 +/- 26.6 microg x h/mL and 28.4 +/- 8.72 microg/mL, respectively, for control samples and 87.7 +/- 30.1 microg x h/mL and 30.0 +/- 8.97 microg/mL, respectively, for St. John's wort treatment samples. St. John's wort administration resulted in no significant effects on the C(max) and AUC of either stereoisomer. A 31% decrease in S(+)-ibuprofen mean residence time (p = 0.02) was observed. CONCLUSIONS: St. John's wort administration for 21 days had no apparent clinically important impact on the single-dose pharmacokinetic parameters of S(+)- and R(-)-ibuprofen. Although St. John's wort treatment appears to significantly reduce the mean residence time of S-ibuprofen, no ibuprofen dose adjustments appear warranted when the drug is administered orally with St. John's wort, due to the lack of significant change observed in ibuprofen AUC and C(max) for either enantiomer.

Ultra-performance liquid chromatographic determination of tocopherols and retinol in human plasma.

A rapid, selective and sensitive ultra-performance liquid chromatography method has been developed for the detection and quantification of tocopherols and retinol in human plasma. Alpha-tocopherol, gamma-tocopherol and retinol are assayed using fluorescence detection. Excitation/emission wavelengths are 295/330 nm and 325/470 nm for the analysis of both tocopherols and retinol, respectively. Retinol acetate is employed as the internal standard. The reversed-phase method incorporates gradient elution with a mobile phase consisting of methanol and acetonitrile. Separation of vitamin compounds is achieved using a bridged ethyl hybrid C18 column. The retention times for retinol, retinol acetate, gamma-tocopherol and alpha-tocopherol are 1.6, 1.8, 3.9 and 4.3 min, respectively. The limits of quantification for retinol, gamma-tocopherol and alpha-tocopherol were 0.02, 0.02 and 0.1 µg/mL, respectively. The assay method is suitable for the analysis of tocopherols and retinol in human plasma. The method may be applied following the ingestion of foods fortified with these fat-soluble vitamins.

Development and pharmacokinetic evaluation of a curcumin co-solvent formulation.

Poor solubility and bioavailability are limiting factors for the clinical application of curcumin. The objective of the current study was to develop a liquid formulation with increased solubility and systemic bioavailability. A co-solvent formulation with increased solubility of 20 mg/ml was developed and optimized. Pharmacokinetics of the new formulation were evaluated using rats receiving 30 mg/kg intravenous or 50 mg/kg intramuscular administration of co-solvent formulation, compared against a control group receiving 50 mg/kg of curcumin in DMSO through intramuscular injection. Plasma concentrations were measured using liquid chromatography-mass spectrometry (LC-MS/MS). The intramuscular injection of formulation resulted in 30% absolute bioavailability and provided sustained release by maintaining plasma concentrations of curcumin above 240 ng/ml for up to 4 h. A 29-fold increase in the maximum plasma concentration (Cmax) and 28-fold increase in the area under the plasma concentration versus time curve (AUC) led to a 28-fold increase in relative bioavailability for the co-solvent formulation. The findings reported here suggest that the clinical application of curcumin can be better-exploited through an intramuscular administration of the co-solvent formulation developed in the present study.