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The National Institute of Standards and Technology offers a variety of natural-matrix and solution-based Standard Reference Materials (SRM) that are characterized for fatty acid composition. The natural-matrix SRM are intended primarily for use as control materials, but other uses include method validation, the development of new analytical methods, and use as a component in achieving traceability of measurements. The use of complex-matrix reference materials for instrument calibration is not recommended; solution calibrants are better suited to this task. In addition to calibration, solution SRM can be used as spiking solutions for fortification of samples, in studying extraction recoveries, for developing chromatographic separations, and as authentic standards for identifying constituents in more complex-matrix extracts. The use of SRM to support the measurement of fatty acids is relevant to a broad spectrum of applications including compliance with and accuracy of nutritional labeling, food manufacturing tolerances (e. g., infant formulas), traceability of measurements for food exports, clinical nutritional measurements, and characterization of alternative energy sources (e. g., biodiesel). Currently, nearly 30 SRM are available with certified, reference, and information values reported for fatty acids. Additional SRM are under development that will complement these reference materials by providing fatty acid profiles in different types of matrices.

Human immunodeficiency virus (HIV)-infected patients often take herbal medicines, which may interact with antiretrovirals. American ginseng induces phase 2 and antioxidant enzymes in vitro and might increase the clearance of zidovudine and/or enhance antioxidant activity. Ten healthy volunteers received 300 mg of zidovudine orally before and after 2 weeks of treatment with a ginsenoside-enriched American ginseng extract 200 mg twice daily. This ginseng extract induced the phase 2 enzyme quinone reductase with an average concentration of doubling of enzyme activity of 190 microg/mL. Total ginsenoside content was 8.5 +/- 0.5%. Pharmacokinetic profiles of zidovudine and oxidative stress marker concentrations were measured post-zidovudine dose. American ginseng does not significantly affect the formation clearance of zidovudine to its glucuronide (ratio post- to pre-American ginseng = 1.17; 90% confidence interval: 0.95-1.45; P = .21), total clearance (ratio = 0.97; 0.82-1.14; P = .70), or plasma zidovudine AUC0-8 (ratio = 1.03; 0.87-1.21; P = .77). Oxidative stress biomarkers are reduced post-American ginseng (F2-isoprostane ratio = 0.79; 0.72-0.86; P < .001; 8-hydroxy-deoxyguanosine ratio = 0.74; 0.59-0.92; P = .02). Two weeks of American ginseng does not alter zidovudine pharmacokinetics but reduces oxidative stress markers.

What is already known about this subject • Only one other study (Becker et al.) has reported on the influence of smoking cessation and smoking resumption on inhaled insulin pharmacokinetics and glucodynamics, concluding that the rapid changes associated with smoking resumption carry the risk for hypoglycaemia and thus should not be used by active smokers. What this study adds • This is the first euglycaemic clamp study on the impact of smoking cessation, acute smoking re-exposure and nicotine replacement on AIR® inhaled insulin pharmacokinetics and glucodynamics. • We demonstrate clinically and statistically significant shifts in glucodynamic response to acute re-exposure to a single cigarette, leading us to conclude that active smokers should be advised against inhaled insulin therapy until smoking abstinence is stable. • Additionally, these results are also the first to demonstrate an apparent independent effect of nicotine replacement therapy on insulin exposure and glucodynamic response. Aims To explore the effects of smoking cessation and acute smoking re-exposure on the pharmacokinetic (PK) and glucodynamic (GD) profiles of AIR® inhaled insulin (AIR Insulin) with or without nicotine replacement therapy (NRT). Methods Nondiabetic smokers (n = 24) with normal pulmonary function completed a two-phase (four-period), open-label, randomized euglycaemic clamp study. During the initial study phase, subjects underwent glucose clamps following AIR Insulin dosing, shortly after smoking, 8–12 h after smoking, or following subcutaneous insulin lispro shortly after smoking. AIR Insulin PK and GD were again assessed during and after a 4-week smoking-cessation period with or without NRT. In the last study period, subjects smoked one cigarette shortly before final AIR Insulin dosing and glucose clamp, to study the effect of acute smoking re-exposure on inhaled insulin PK and GD. Results Compared with the preceding active smoking phase, the administration of AIR Insulin in nondiabetic subjects undergoing a 4-week period of smoking abstinence resulted in a decrease in PK and GD of approximately 25% (P = 0.008 for both), an effect which was greater in subjects using NRT. Following rechallenge with a single cigarette (without NRT), GD response to AIR Insulin increased significantly (P = 0.006) towards precessation levels, relative to smoking abstinence. In subjects using NRT, however, the increase in GD was less pronounced. Conclusion Smoking, smoking cessation and acute re-exposure with a single cigarette are associated with clinically significant alterations in AIR Insulin pharmacokinetics and glucodynamics. AIR Insulin should not be used by smokers or those at risk for recidivism.

What is already known about this subject • Atomoxetine is a cytochrome P450 2D6 (CYP2D6) substrate and its pharmacokinetics has been characterized in a predominantly White population during clinical development. • There are scant East Asian pharmacokinetic data available. • The CYP2D6*10 allele is particularly prevalent in East Asian populations and may contribute to the known ethnic differences in CYP2D6 metabolic capacity. What this study adds • The pharmacokinetics of multiple-dose 80 mg daily atomoxetine observed in Chinese healthy subjects appears comparable to previous data in other ethnic populations. • Homozygous CYP2D6*10 subjects appear to have higher exposures, but are not a clearly distinct group compared with other CYP2D6 extensive metabolizers. Aims To characterize atomoxetine pharmacokinetics, explore the effect of the homozygous CYP2D6*10 genotype on atomoxetine pharmacokinetics and evaluate the tolerability of atomoxetine, in healthy Chinese subjects. Methods Twenty-four subjects, all CYP2D6 extensive metabolizers (EM), were randomized to receive atomoxetine (40 mg qd for 3 days, then 80 mg qd for 7 days) or matching placebo (2 : 1 ratio) in a double-blind fashion. Atomoxetine serum concentrations were measured following single (40 mg) and multiple (80 mg) doses. Adverse events, clinical safety laboratory data and vital signs were assessed during the study. Results Atomoxetine was rapidly absorbed with median time to maximum serum concentrations of approximately 1.5 h after single and multiple doses. Atomoxetine concentrations appeared to decrease monoexponentially with a mean apparent terminal half-life (t1/2) of approximately 4 h. The apparent clearance, apparent volume of distribution and t1/2 following single and multiple doses were similar, suggesting linear pharmacokinetics with respect to time. Homozygous CYP2D6*10 subjects had 50% lower clearances compared with other EM subjects, resulting in twofold higher mean exposures. No clinically significant changes or abnormalities were noted in laboratory data and vital signs. Conclusions The pharmacokinetics of atomoxetine in healthy Chinese subjects appears comparable to other ethnic populations. Multiple dosing of 80 mg qd atomoxetine was well tolerated in this study.

A polymer-based RP sorbent was prepared by immobilizing a poly(ethylene-co-acrylic acid) copolymer with an acid mass fraction of 5% on silica by using a 3-glycidoxypro-pyl linkage. 13 C cross-polarization/magic angle spinning NMR spectroscopy of the sorbent, either in the dry state or suspended in the mobile phase, showed an increase in mobility at elevated temperatures. Alkyl chain segments with gauche conformations were more mobile than chain segments with trans conformations. The strength of the 13 C- 1 H dipolar couplings in the alkyl chains was measured using the constant time dipolar and chemical shift pulse sequence, revealing less molecular motion for the trans conformation. Non-linear van't Hoff plots were observed for separations of shape-constrained solutes (such as geometric β-carotene isomers and polycyclic aromatic hydrocarbons). At higher temperatures, the retention behavior was similar to that of monomeric C 18 sorbents, whereas at ambient and lower temperatures, enhanced shape-selective properties were exhibited similar to those of polymeric C 30 sorbents.

Aims The aim of this study was to evaluate the effect of rifampicin co-administration on the pharmacokinetics of ruboxistaurin and its active metabolite, N-desmethyl ruboxistaurin and, in addition, to compare the changes in pharmacokinetics of ruboxistaurin and N-desmethyl ruboxistaurin with the urinary 6β-hydroxycortisol : cortisol ratio. Ruboxistaurin is a specific protein-kinase-C β inhibitor in clinical development for the treatment of diabetic microvascular complications. Methods This was a two-period, one-sequence study. Sixteen healthy male subjects completed both study periods. In period one, a single 64 mg oral dose of ruboxistaurin was administered. In period two, 600 mg rifampicin was administered daily for 9 days, during which another single 64 mg ruboxistaurin dose was administered on day 7. Blood samples were collected and assayed for ruboxistaurin and N-desmethyl ruboxistaurin. CYP3A4 induction was assessed by ratios of urinary 6β-hydroxycortisol : cortisol (6β-OHC : C) obtained via 24 h and morning-spot sampling techniques. Results Following repeated doses of rifampicin, both the mean Cmax and AUC(0,∞) of ruboxistaurin were significantly reduced by approximately 95% (P ≤ 0.001). For the metabolite, the mean Cmax decreased by 68% (P ≤ 0.001), and AUC(0,∞) decreased by 77% (P ≤ 0.001). The tmax values did not appear affected. The 6β-OHC : C ratios from both 24 h and morning spot methods increased significantly, consistent with CYP3A4 induction. Conclusions The effect of rifampicin co-administration on the exposure of ruboxistaurin is consistent with ruboxistaurin being a substrate of CYP3A4. Therefore, co-administration with known CYP3A4 inducing agents (rifampicin, carbamazepine, phenobarbital, etc.) may decrease the concentrations of ruboxistaurin and N-desmethyl-ruboxistaurin. In this study, 6β OHC : C ratios substantially underestimated the impact of rifampicin on ruboxistaurin.

This open-label study investigated the effect of exenatide coadministration on the steady-state plasma pharmacokinetics of digoxin. A total of 21 healthy male subjects received digoxin (day 1, 0.5 mg twice daily; days 2-12, 0.25 mg once daily) and exenatide (days 8-12, 10 μg twice daily). Digoxin plasma and urine concentrations were measured on days 7 and 12. Exenatide coadministration did not change the overall 24-hour steady-state digoxin exposure (AUC τ , s s ) and C m i n , s s but caused a 17% decrease in mean plasma digoxin C m a s , s s (1.40 to 1.16 ng/mL) and an increuse in digoxin t m a x , s s (median increase, 2.5 hours). Although the decrease in digoxin C m a x , s s was statistically significant, peak concentrations were within the therapeutic concentration range in all subjects. Digoxin urinary pharmacokinetic parameters were not altered. Gastrointestinal symptoms, the most common adverse effects of exenatide, decreased over time. Exenatide administration does not cause any changes in digoxin steady-state pharmacokinetics that would be expected to have clinical sequelae; thus, dosage adjustment does not appear warranted, based on pharmacokinetic considerations.

Aim To compare the pharmacokinetic profiles and dose proportionality of olanzapine in Chinese and Caucasian subjects. Methods Randomized, three-period study with 12 Chinese and 12 Caucasian, healthy, male subjects administered 2.5, 5 and 10 mg olanzapine. Noncompartmental pharmacokinetic parameters were derived. Results No statistically significant racial differences in the weight-normalized pharmacokinetic parameters were observed except for Vz/Fnorm, which was 17% lower at the 5- and 10-mg dose in the Chinese group (95% confidence interval 8.49, 10.1 and 8.05, 9.73, respectively), compared with the Caucasian group (9.53, 12.8 and 9.39, 12.0, respectively). Olanzapine's pharmacokinetics were linear and dose proportional in both racial groups. Conclusion The pharmacokinetics of olanzapine are similar in both Chinese and Caucasian racial groups.

A new Standard Reference Material (SRM) for use in characterizing general aspects of liquid chromatographic column performance is described. SRM 870 Column Performance Test Mixture for Liquid Chromatography contains five components: uracil, toluene, ethylbenzene, quinizarin, and amitriptyline, and is intended to provide indications of column void volume, hydrophobicity, methylene selectivity, activity toward organic bases, and activity toward metal chelators. The test is performed under neutral, buffered conditions. The measurement of retention and peak asymmetry factors for the components facilitates column classification. It is anticipated that this material will be useful (1) in column selection during method development, (2) as a control material to monitor column performance over time, and (3) in quality control in column manufacturing.

Since the establishment of the Marine Corps Recruit Depot, Parris Island, the command has been dealing with an archaeological site that dates from 1562 that contains the remains of Spanish and French colonial settlements. Known as the Santa Elena/Charlesfort site, the area has been under excavation since the early 1920s. Because of its importance to the colonial history of the United States, the site has been designated a national landmark. Besides its cultural importance, the site has also served as a learning tool for the Depot in its care and handling of cultural resources. © 2003 Wiley Periodicals Inc.

Aims To test the hypothesis that the renal clearance of moxonidine decreases when dosed with quinidine. Methods A randomized, two-period study was conducted with six healthy, male subjects orally dosed with either 0.2 mg moxonidine alone or 1 h after 400 mg quinidine sulphate. Pharmacokinetic parameters were calculated using a noncompartmental analysis method. Results When coadministered, quinidine significantly increased moxonidine AUC and t1/2 by 11% and 15%, respectively, and decreased CL/F by 10% compared with the control dosing. CLR and Aeur were not significantly different. Clinically, both treatments were well tolerated. Conclusions Quinidine does not affect the renal clearance of moxonidine. The decrease in apparent total clearance of moxonidine with quinidine coadministration was possibly due to metabolic inhibition, though not likely to be clinically significant.

Relationships between column temperature and retention behavior are reviewed for separations in reversed-phase liquid chromatography on hydrocarbonaceous bonded phases. Changes in selectivity are observed to occur with changes in temperature for a wide variety of stationary phase types. The largest temperature effects are observed for long alkyl chain length stationary phases and liquid crystalline stationary phases. Changes in stationary phase conformational structure are characterized by spectroscopic approaches, and correlations are made with retention behavior. In general, improved separations of isomers are usually possible at reduced column temperature. Applications are presented for classes of compounds that exhibit well-defined (constrained) molecular structure.

A micellar electrokinetic chromatographic (MEKC) separation system was developed for the efficient separation of biologically and clinically important green tea catechins. Six structurally isomeric tea catechins, e.g., (−)epigallocatechin-3-gallate (EGCG), (−)epicatechin gallate (ECG), (−)gallocatechin gallate (GCG), (−)epigallocatechin (EGC), (−)epicatechin (EC), and (+)catechin (C), were effectively separated using a tetraborate/sodium dodecyl sulfate (SDS)/β-cyclodextrin micellar buffer system. The effects of several critical separation parameters (micelle charge type, surfactant type, organic solvent buffer modifier, micelle concentration, buffer pH, and cyclodextrin buffer modifier) were evaluated for enhanced isomer separation and resolution. The pH was shown to be a strong factor influencing the separation of the isomers, but baseline resolution of all six structural isomers was only effected when a micellar buffer system contained β-cyclodextrin buffer modifier. The proficiency of the developed method was tested by determining the analytical levels (mg/g) of crude catechins in aqueous extractions of three varieties of green tea (Camellia sinesis). © 1998 John Wiley & Sons, Inc. J Micro Sep 10: 671–679, 1998

The retention behavior of polycyclic aromatic hydrocarbons (PAHs) in packed-column supercritical fluid chromatography (SFC) is studied for monomeric and polymeric C18 columns. Molecular shape discrimination (shape selectivity) is assessed through the use of Standard Reference Materials (SRMs), adn changes in selectivity are studied as a function of temperature, pressure, and mobile phase composition. Examples of separations of complex PAH isomer mixtures are presented, and guidelines are provided for modification and optimization of shape selectivity in SFC.

Selectivity for polychlorinated biphenyl (PCB) congeners was examined for a series of cyanobiphenyl stationary phases, and the results were compared to a nonpolar 5% phenyl methylpolysiloxane phase and a shape-selective smectic liquid crystalline phase. For all of the columns studied, the degree of ortho substitution of the congener was found to be a significant factor controlling chromatographic retention of PCBs. The retention pattern on six different cyanobiphenyl phases followed the same general pattern as on the liquid crystalline column, though the trends were more exaggerated on the liquid crystalline phase. While the general retention pattern was similar for all of the cyanobiphenyl phases studied, subtle differences were observed, resulting in significant selectivity differences. For isomeric planar PCB congeners, elution order could be correlated to length-to-breadth ratios. Among the cyanobiphenyl phases, the p,p- and the o,p,p-cyanobiphenyl phases had the greatest enhancement of retention for planar congeners. A shapeselective test mixture reflected the similarity of retention on the cyanobiphenyl phases to both the 5% phenyl methylpolysiloxane phase and the smectic liquid crystalline phase. © 1995 John Wiley & Sons, Inc.

A novel p,p-cyanobiphenyl stationary phase (p-cyanobiphenyl, p-allyloxy methylpolysiloxane) has been evaluated for the GC investigation of polychlorinated biphenyls (PCBs). Several PCB congeners which coelute on the phases typically used for PCB analysis (e.g. 5% phenyl methylpolysiloxane) are separated on the p,p-cyanobiphenyl phase, including the hexachlorobiphenyl congeners PCB 163, PCB 164, and PCB 138. In this work, a p,p-cyanobiphenyl stationary phase was used to measure selected PCB congeners in two Standard Reference Materials (SRMs) available from the National Institute of Standards and Technology (NIST), and two Certified Reference Materials (CRMs) available from the Community Bureau of Reference (BCR). The materials analyzed were SRM 1588, Organics in Cod Liver Oil; SRM 1945, Organics in Whale Blubber; CRM 349, Chlorobiphenyls in Cod Liver Oil; and CRM 350, Chlorobiphenyls in Mackerel Oil. Concentrations are reported for several PCB congeners which coelute on the 5% phenyl methylpolysiloxane, including PCB 163 and PCB 164.

Column selectivity is examined for a series of smectic liquid crystalline columns and is compared with methyl and C18 polysiloxane columns for the separation of polycyclic aromatic hydrocarbon (PAH) isomers. A set of extended and condensed solute probes is described that provides a sensitive indication of variations in column shape selectivity. Examples of shape selectivity differences are presented for smectic liquid crystalline columns and 5% phenyl polysiloxane columns using various PAH isomer sets. Variations in selectivity have been observed among different smectic liquid crystalline columns, and this problem appears more significant than for methyl polysiloxane columns. The selectivity ration for tetraphenylmethane and p-terphenyl provides a sensitive indication of column shape selectivity, with a change in elution order occurring between ordered (smectic liquid crystalline) columns and non-ordered (methyl polysiloxane) columns. Shape selectivity differences indicated by this test mixture are apparent for more complex PAH isomer mixtures. Despite stationary phase selectivity variability, smectic liquid crystalline columns offer considerable potential for solving difficult separation problems involving structured solutes.

A compact analytical instrument is described which allows microsamples to be extracted with supercritical fluids, and the extract preconcentrated and analyzed by capillary supercritical fluid chromatography in a single coupled unit. Thus, no off-line sample pretreatment is required, and the possibility of extraneous contamination is reduced. To achieve greater selectivity and sensitivity for selected species, three different detectors (UV absorption, flame ionization and electron capture) were all connected on-line. This analytical instrument configuration was established by upgrading a commercial capillary supercritical fluid chromatograph using regular chromatographic supplies. To illustrate the analytical utility of this hyphenated technique, an assortment of compounds that are not easily determined by traditional gas chromatographic or liquid chromatographic methods was selected: explosives, propellants, and related species. The instrumental design, as well as selected analytical conditions (sample pretreatment, extraction, preconcentration, separation, and detection) were investigated to improve selectivity and/or sensitivity. The determination of explosive residues on soil is described as an environmental analysis application of the system. Detection limits for some compounds are estimated to be as low as 100 pg. The firearm propellants were characterized through their extractable organic constituents, and the usefulness of such characterization in forensic investigations is discussed. Closely related to this issue is the analysis of the residue in expended cartridge cases. A chromatographic fingerprint was obtained from the propellant used in the ammunition. This fingerprint can be used under certain circumstances to correlate a specific batch of propellant with the residue left in a fired cartridge case.

An empirical test is described for the evaluation of column selectivity in reversed-phase liquid chromatography. Using a test mixture of three polycyclic aromatic hydrocarbons (PAH), overall column selectivity toward PAH was assessed for over 20 different commercial C18 columns. Retention behavior was correlated to phase type (i.e., monomeric and polymeric surface modification chemistry) for custom synthesized phases. A classification scheme is proposed in which commercial C18 columns are grouped into three classes based on retention behavior: monomeric-like, polymeric-like, and intermediate phase selectivity toward PAH. Correlation of retention behavior of the test mixture with the separation of PAH mixtures and with more general column properties (e.g., phase thickness) is discussed.

Reversed-phase liquid chromatography (LC) on C18 stationary phases provides excellent selectivity for the separation of polycyclic aromatic hydrocarbons (PAH). Recent studies have shown that several factors affect selectivity for the LC separation of PAH including phase type (monomeric or polymeric), pore diameter and surface area of the silica substrate, and surface density of the C18 ligands. In this paper the separation of eleven PAH isomers of molecular weight 278 is used to further illustrate the effect of stationary phase characteristics and shape of the solute (length-to-breadth ratio, L/B) on retention and selectivity. Only polymeric C18 phases with a high C18 surface coverage provided separation of all eleven isomers and the elution order of these isomers generally followed increasing L/B values. The effect of solute nonplanarity on reversed-phase LC retention was investigated on both monomeric and polymeric phases using a series of planar and nonplanar PAH pairs. For each solute pair, the nonplanar solute eluted earlier than the planar solute, the largest selectivity factors being observed on the C18 phase with the highest percent carbon load. Based on these studies, a model is proposed to describe the retention of PAH on polymeric C18 phases.

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