Effect of Sunscreen Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.

Importance: The US Food and Drug Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic carcinogenicity and additional developmental and reproductive studies. Objective: To determine whether the active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) of 4 commercially available sunscreens are absorbed into systemic circulation. Design, Setting, and Participants: Randomized clinical trial conducted at a phase 1 clinical pharmacology unit in the United States and enrolling 24 healthy volunteers. Enrollment started in July 2018 and ended in August 2018. Interventions: Participants were randomized to 1 of 4 sunscreens: spray 1 (n = 6 participants), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two milligrams of sunscreen per 1 cm2 was applied to 75% of body surface area 4 times per day for 4 days, and 30 blood samples were collected over 7 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, and ecamsule. Results: Among 24 participants randomized (mean age, 35.5 [SD, 1.5] years; 12 (50%] women; 14 [58%] black or African American; 14 [58%]), 23 (96%) completed the trial. For avobenzone, geometric mean maximum plasma concentrations were 4.0 ng/mL (coefficient of variation, 6.9%) for spray 1; 3.4 ng/mL (coefficient of variation, 77.3%) for spray 2; 4.3 ng/mL (coefficient of variation, 46.1%) for lotion; and 1.8 ng/mL (coefficient of variation, 32.1%). For oxybenzone, the corresponding values were 209.6 ng/mL (66.8%) for spray 1, 194.9 ng/mL (52.4%) for spray 2, and 169.3 ng/mL (44.5%) for lotion; for octocrylene, 2.9 ng/mL (102%) for spray 1, 7.8 ng/mL (113.3%) for spray 2, 5.7 ng/mL (66.3%) for lotion, and 5.7 ng/mL (47.1%) for cream; and for ecamsule, 1.5 ng/mL (166.1%) for cream. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash, which developed in 1 participant with each sunscreen. Conclusions and Relevance: In this preliminary study involving healthy volunteers, application of 4 commercially available sunscreens under maximal use conditions resulted in plasma concentrations that exceeded the threshold established by the FDA for potentially waiving some nonclinical toxicology studies for sunscreens. The systemic absorption of sunscreen ingredients supports the need for further studies to determine the clinical significance of these findings. These results do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.

Development and validation an LC-MS/MS method to quantify (+)-borneol in rat plasma: Application to a pharmacokinetic study.

(+)-Borneol, a bicyclic monoterpene, has been shown to possess valuable biological properties and potential as a pharmaceutical agent due to anti-inflammatory, anti-oxidant and GABA receptor-enhancing functions; it also enhances the permeability of the blood brain barrier to improve the efficacy of CNS drugs. In this study, we have developed a simple, selective, and rapid liquid chromatography-tandem mass spectrometry method for the assay of (+)-borneol in rat plasma. Verapamil was used as an internal standard. Plasma samples were deproteinized using methanol. The analyte was detected by a mass spectrometer with positive atmospheric pressure chemical ionization by multiple reaction monitoring mode for transitions at m/z [M + H]+ 137.2 → 81.0 for (+)-borneol and 455.2 → 165.1 for verapamil. The method has been fully validated to ensure good selectivity, a satisfactory lower limit of quantification at 10.0 ng/mL, acceptable intra- and inter-day accuracy, and high precision. The method was used for the pharmacokinetic evaluation of (+)-borneol in Sprague-Dawley rats after intravenous, oral, and sublingual administration. The results indicate that oral bioavailability of (+)-borneol was extremely low but sublingual administration yielded rapid absorption and favorable bioavailability of (+)-borneol.

Tanshinol borneol ester on nanostructured lipid carriers has longer brain and systemic effector retention and better antioxidant activity in vivo.

BACKGROUND: Tanshinol borneol ester (DBZ) is a hybrid of danshensu (DSS) and borneol and has anti-ischemic activity in animals. However, its low water solubility and short half-life limit its clinical application. METHODS: We prepared polyethylene glycol (PEG)-modified and DBZ-loaded nanostructured lipid carriers (DBZ-PEG-NLC) and DBZ-NLC, and examined their physical characteristics, such as particle size, zeta potential, entrapment efficiency and drug loading. The in vitro stability and pharmacokinetics in rats as well as antioxidant activity of DBZ-PEG-NLC and DBZ-NLC in a C57BL/6 mouse model of ischemia/reperfusion-related brain injury were investigated. The levels of DBZ and its hydrolyzed DSS in rat plasma and brain microdialysates were determined by liquid chromatography-mass spectroscopy/mass spectroscopy analysis. RESULTS: We found that the mean particle size and entrapment efficacy of DBZ-PEG-NLC were similar to that of DBZ-NLC. The DBZ-PEG-NLC, like DBZ-NLC, released DBZ in a biphasic manner with initially burst release and then prolonged slow release in vitro. Intravenous injection of DBZ-PEG-NLC resulted in significantly higher levels and longer retention periods of DBZ and DSS in plasma and the brains than DBZ-NLC and DBZ in rats. Finally, treatment with DBZ-PEG-NLC achieved a better antioxidant activity than DBZ or DBZ-NLC in mouse model of ischemia/reperfusion by reducing the levels of brain malondialdehyde, but increasing the levels of brain superoxide dismutase and glutathione. CONCLUSION: DBZ-PEG-NLC is a preferable option to deliver DBZ for sustainable release of DSS and borneol in vivo, and may serve as a promising drug for effective therapy of ischemic cardiovascular and cerebrovascular diseases.

[Distribution of 4-methyl-2,6-diisobornylphenol in rat tissues].

We have studied the distribution of the new compound 4-methyl-2,6-diisobornylphenol in rats after a single oral administration in a dose of 20 mg/kg. The pharmacokinetic parameters have been estimated by the noncompartmental method. It is established that the drug is nonuniformly distributed in the body and has a high affinity for liver and heart. A low penetration of 4-methyl-2,6-diisobornilphenol has been found in brain tissue. The accumulation of 4-methyl-2,6-diisobornilphenol in adipose tissues has not been found. It been showed that the drug is slowly eliminated from the body, especially from the heart tissues for which the mean retention time is MRT = 45 h.

Simultaneous determination of four volatile compounds in rat plasma after oral administration of Shexiang Baoxin Pill (SBP) by HS-SPDE-GC-MS/MS and its application to pharmacokinetic studies.

In this study, a headspace, solid-phase dynamic extraction method coupled to gas chromatography-tandem mass spectrometry (HS-SPDE-GC-MS/MS) method was developed for the simultaneous determination of four volatile compounds, namely, isoborneol, borneol, muscone and cinnamaldehyde, in rat plasma after oral administration of Shexiang Baoxin Pill (SBP) using naphthalene as an internal standard (IS). The target compounds were extracted using an SPDE needle device coated with a poly (dimethylsiloxane) (PDMS) phase. The detection was achieved by GC-MS/MS in multiple reaction monitoring (MRM) mode. The optimised mass transition ion pairs (m/z) for quantitation were 95.1/67.1 for isoborneol and borneol, 85.0/67.0 for muscone, 131.0/77.0 for cinnamaldehyde and 128.1/102.1 for the IS. The parameters that affect the extraction ratio, such as the pre-incubation time, extraction temperature, number of extraction cycles, desorption volume and pH, were also optimised. The method was thoroughly validated with respect to specificity, linearity, precision, accuracy, recovery and stability. A sufficiently sensitive HS-SPDE-GC-MS/MS method was first developed in this study to determine the pharmacokinetics of volatile compounds found in rat plasma following oral administration of SBP. The method developed uses a simple procedure for plasma sample preparation and could be a promising tool for the analysis of complex volatile samples, such as traditional Chinese medicine (TCM).

The effect of borneol on the concentration of meropenem in rat brain and blood.

Meropenem is a carbapenem antibiotic with a wide spectrum of activity against both Gram-positive and Gram-negative bacteria. Because of its clinical efficacy, meropenem is an excellent choice for the treatment of serious infections in both adults and children. The knowledge of tissue concentrations of antibiotic in an infection site is valuable for the prediction of treatment outcome. The aim of the present study is to investigate the effect of borneol on the concentration of meropenem in rat brain and blood and to find the potential relationships of the combined use of medicine and traditional Chinese medicine. Analysis of meropenem in the dialysates was achieved using the microdialysis technique and HPLC. At 40 min after the administration of an intraperitoneal injection of meropenem, the concentration of meropenem in brain in borneol+meropenem group was 2.25 (0.35) µg ml(-1), which was significantly higher than that in meropenem group [1.20 (0.12) µg ml(-1); P < 0.01]. Within 80 min of drug administration, the AUCbrain/AUCblood (area under the curve, AUC) in the borneol+meropenem group was 1.2 times that of the meropenem group. Borneol can increase the concentration of meropenem in the cerebrospinal fluid, but has no influence on its blood concentration. This study represents a successful application of the microdialysis technique, which is an effective method for the study of pharmacokinetics of meropenem.

[Evaluation of the linearity of pharmacokinetics of the phenolic antioxidant 4-methyl-2,6-diisobornylphenol upon intragastric administration].

The linearity of pharmacokinetics of 4-methyl-2,6-diisobornylphenol after single intragastric administration in doses within 10 - 200 mg/kg has been studied in rats. It has been established that pharmacokinetics of 4-methyl-2,6-diisobornilphenol in the indicated dose range is not linear due to a limited absorption of the drug from the intestine.

An ultrasensitive chemiluminescent method for the tanshinol borneol ester determination and its pharmacokinetic analysis.

Tanshinol borneol ester (DBZ), a chemical combination of danshensu and borneol, is an experimental drug that exhibits efficacious anti-ischemic activity in animal models. In this work, an ultrasensitive chemiluminescence (CL) method for the determination of DBZ was established based on the inhibitory effect of DBZ on the CL signal produced from the reaction between potassium permanganate and luminol in alkaline solution. The CL intensity responded linearly to the concentration of DBZ in the range 2.0 × 10(-10) to 4.0 × 10(-8) g/mL with a detection limit of 7 × 10(-11) g/mL. The relative standard deviation (RSD) was 3.8% for 4.0 × 10(-9) g DBZ (n = 11). The proposed method showed characteristics of high sensitivity, simple device and quick. In addition, this proposed method had been applied satisfactorily to the analysis of DBZ in blood. The pharmacokinetics of DBZ in rat has also been studied using the CL method.

The mechanism of the opening of the blood-brain barrier by borneol: a pharmacodynamics and pharmacokinetics combination study.

ETHNOPHARMACOLOGICAL RELEVANCE: Borneol is widely used in traditional Chinese medicine to facilitate the distribution of central nervous system (CNS) drugs in brain due to its ability to open blood-brain barrier (BBB), however, the underlying mechanism is still unclear. In this study, the effect of borneol on different brain regions were investigated to explore the mechanism. MATERIALS AND METHODS: After oral administration of borneol (0.1, 0.2 g/kg) for seven consecutive days, SD rats were injected with Rh123 (1.0 mg/kg). The concentrations of Rh123 were detected in four brain regions of cortex, hippocampus, hypothalamus and striatum by a small animal vivo imaging system and a fluorescence microplate reader respectively. The ultrastructures of BBB were examined. Moreover, the expressions of the four transporters of ATP-binding cassette (ABC) family, multidrug resistance 1a (Mdr1a), multidrug resistance 1b (Mdr1b), multidrug resistance protein 1 (Mrp1), Mrp4, Mrp5 and breast cancer resistance protein (Bcrp) in the four brain regions were analyzed. Finally, the deliveries of borneol in the plasma and the four brain regions were examined by a pharmacokinetics study. RESULTS: Administration of 0.2 g/kg borneol produced loose structure in the tight junction and void structure between the endothelial cell and mesangial cell. Borneol at 0.1 g/kg and 0.2 g/kg increased the delivery of Rh123 in hippocampus and hypothalamus obviously. Permeability index followed a similar trend. Protein expression assays showed that borneol decreased the expression of Mdr1 and Mrp1 in hippocampus and hypothalamus. Further RT-PCR study showed that borneol decreased the expressions of both Mdr1a and Mdr1b in hippocampus and hypothalamus. The pharmacokinetics study demonstrated that the delivery of borneol in cortex was the most and that in striatum the least, with the deliveries of borneol in hippocampus and hypothalamus in between. CONCLUSIONS: Borneol showed tissue specific BBB-opening effect, which was associated with its regulation of the ultrastructure of brain tissues and the expressions of Mdr1a, Mdr1b and Mrp1. The present study indicated that borneol should be used in concert with drugs targeting hippocampus or hypothalamus to exert its synergistic effect to the maximum.

Comparative pharmacokinetic studies of borneol in mouse plasma and brain by different administrations.

Borneol, a monoterpenoid alcohol, is used widely, particularly in combined formulas for preventing and curing cardiovascular and cerebrovascular diseases in traditional Chinese medicine. In order to understand the blood and brain pharmacokinetics after intravenous, intranasal, or oral administration and to investigate the superiority and feasibility of intranasal administration, a simple gas chromatographic (GC) method with flame ionization detection (FID) was developed for the quantification of borneol. Blood samples and brain were collected from mice at 1, 3, 5, 10, 20, 30, 60, 90, and 120 min after intravenous, intranasal, or oral administration of borneol at a dosage of 30.0 mg/kg. Sample preparations were carried out by liquid-liquid extraction with an internal standard solution of octadecane. The pharmacokinetic parameters were calculated by the software of Kinetica. The calibration curves were linear in the range of 0.11-84.24 µg/ml and 0.16-63.18 µg/g for borneol in plasma and brain, respectively. The methodological and extraction recoveries were both in the range of 85%-115%. The intra-day and inter-day variabilities for plasma and brain samples were ≤5.00% relative standard deviation (RSD). The absolute bioavailabilities F of intranasal and oral administrations were 90.68% and 42.99%. The relative brain targeted coefficients Re of intranasal and oral administrations were 68.37% and 38.40%. The GC-FID method developed could be applied to determination and pharmacokinetic study. The borneol from injection was distributed and metabolized fast without absorption process. The borneol from oral administration was distributed more slowly and had the lowest absolute bioavailability. Nasal administration of borneol was quickly absorbed into the blood and brain, was easy to use and had a greater safety than infection, which makes it worthy of further development as an administration route for encephalopathy treatment.

[Pharmacokinetics of phenolic antioxidant 4-methyl-2,6-diisobornylphenol upon intravenous injection].

The pharmacokinetics of 4-methyl-2,6-diisobornylphenol (MDIBP) in rat blood plasma has been studied after intravenous injection. The drug concentration in the plasma was determined using a reverse-phase HPLC procedure. It is shown that MDIBP rapidly penetrates into intensively perfused organs, but is slowly eliminated from the organism (MRT value amounting to 9 h).

Pharmacokinetic study of borneol and menthol in rats after oral administration of qingyan drop pills.

Both borneol and menthol are bioactive substances derived from Chinese herbal medicines. In order to understand the pharmacokinetics of borneol and menthol in Qingyan drop pills, a rapid, sensitive, and simple gas chromatographic (GC) method with flame ionization detection (FID) was developed for the simultaneous determination of borneol and menthol in rat plasma. Sample preparations were carried out by liquid-liquid extraction (LLE) with an internal standard solution of naphthalene. The analytes and internal standard (IS, naphthalene) were separated well on an HP-1 capillary column. The pharmacokinetic parameters were estimated by a compartmental method using the Phoenix WinNonlin software program (Version 6.0). The standard curves were linear over a wide concentration range of 2.5-50.0 ng/µL ( R = 0.9963), 8.7-62.2 ng/µL ( R = 0.9994) for both borneol and menthol in plasma, respectively. The limits of quantification (LOQ) of borneol and menthol in plasma were 2.4 ng/µL and 5.0 ng/µL, respectively. The intra-day precisions for borneol and menthol were < or = 10.0 % R. S. D. at the LOQ and < or = 6.0 % at higher concentrations. The average value of CMAX was 18.97 ± 2.71 ng/µL with a TMAX at 20.00 ± 0.00 min for borneol after oral administration of the drop pills; for menthol, the average value of CMAX was 79.02 ± 11.40 ng/µL with a TMAX at 25.00 ± 4.40 min. This validated assay method was successfully applied to a pharmacokinetic study of borneol and menthol after oral administration of Qingyan drop pills in rat. The results showed that the kinetics of borneol and menthol can be described by an open one-compartment model. The pharmacokinetic parameters provide some information for clinical administration of Qingyan drop pills.

A simple gas chromatographic method for the simultaneous determination and pharmacokinetic study of tetramethylpyrazine phosphate and borneol in mouse plasma and brain tissue after oral administration of the fufang tetramethylpyrazine phosphate tablets.

A rapid, sensitive, and simple gas chromatographic method with flame ionization detection is developed for the simultaneous determination of tetramethylpyrazine phosphate (TMPP) and borneol in mouse plasma and brain tissue. Sample preparations are carried out by deproteinization with an internal standard solution in methanol. The analytes and internal standard (dimethyl sulfoxide) are well-separated on an HP-5 MS capillary column. The analytical curves are linear over a wide concentration range of 0.02-40 microg/mL for both TMPP and borneol in plasma and brain tissue, with the intra- and inter-day precision (the relative standard deviation values) at less than 15%. TMPP and borneol are both stable under different conditions. The method described is successfully applied to the pharmacokinetic study of mouse plasma and brain tissue after oral administration of the Fufang TMPP and TMPP tablets to mice.

Pharmacological evaluation of a novel cannabinoid 2 (CB2) ligand, PF-03550096, in vitro and in vivo by using a rat model of visceral hypersensitivity.

Previous studies have shown that cannabinoid 2 (CB(2))-receptor agonists might have analgesic effects on visceral hypersensitivity. To extend these results, we have determined the pharmacological characteristics of a newly designed CB(2) ligand, N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide (PF-03550096), in vitro and in vivo. PF-03550096 showed high affinity to human (K(i) = 7.9 +/- 1.7 nM) and rat CB(2) receptors (K(i) = 47 +/- 5.6 nM). In a cell-based functional assay, PF-03550096 behaved as a full agonist and showed high selectivity for human CB(2) receptors. Orally administered PF-03550096 (3, 10 mg/kg) inhibited the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced decrease in colonic pain threshold with statistical significance. The inhibitory effect of PF-03550096 (10 mg/kg) was significantly reversed by a selective CB(2) antagonist, N-(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl-5-(4-chloro-3-methylphenyl)-1(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528), while SR144528 itself did not modify colonic pain threshold. These results indicate that PF-03550096 is a potent CB(2) agonist and possesses efficacy in a rat model of visceral hypersensitivity.

Peripherally administered non-peptide oxytocin antagonist, L368,899, accumulates in limbic brain areas: a new pharmacological tool for the study of social motivation in non-human primates.

Central administration of oxytocin (OT) antagonists inhibits maternal and sexual behavior in non-primates, providing the strongest experimental evidence that endogenous OT facilitates these behaviors. While there have been a few reports that ICV administration of OT increases social behaviors in monkeys, no studies to date have assessed the effects of OT antagonists. Therefore, we studied in rhesus monkeys whether L368,899, a non-peptide antagonist produced by Merck that selectively blocks the human uterine OT receptor, penetrates the CNS after peripheral administration and alters female maternal and sexual behavior. In two studies in four male monkeys, L368,899 was injected iv (1 mg/kg) after which (1) CSF samples were collected at intervals over 4 h and (2) brains were collected at 60 min. Assay of samples confirmed that iv-administered L368,899 entered CSF and accumulated in the hypothalamus, septum, orbitofrontal cortex, amygdala and hippocampus, but not other areas. An adult female monkey was tested for interest in either an infant or sexual behavior, receiving a different iv treatment prior to each test (1 or 3 mg/kg of L368,899 or saline). OT antagonist treatment reduced or eliminated interest in the infant and sexual behavior. These results, although preliminary, are the first to directly implicate endogenous OT in activation of primate maternal interest and sexual behavior. While it remains to be empirically demonstrated that peripherally administered L368,899 blocks central OT receptors, our behavioral findings suggest that this non-peptide antagonist may facilitate testing OT involvement in a variety of social and other behaviors in primates.

Influence of food on the oral bioavailability of deramciclane from film-coated tablet in healthy male volunteers.

The effect of a high-fat meal on the oral bioavailability of deramciclane 30 mg tablet was evaluated in 18 healthy male volunteers in a randomised, single dose, two-way crossover study. The drug was administered following an overnight fast or a standardised high-fat breakfast. The plasma concentrations of deramciclane and N-desmethylderamciclane were determined by using a validated HPLC-MS -MS/MS method. An effect of food on the bioavailability was indicated if the 90% confidence interval (CI) for the ratio of geometric means of fed and fasted treatments was not contained in the equivalence limit of 0.8-1.25 for AUC and C(max). The ratios of the mean C(max) and AUC(0-infinity) values of deramciclane were 1.24 (90% CI 1.12-1.38) and 1.31 (90% CI 1.21-1.41) in fed versus fasted subjects, which overlapped but exceeded the equivalence limit. In contrast to the parent compound, the 90% CI of the mean ratios for AUC(0-infinity) and C(max) of N-desmethylderamciclane were within the predefined range. The 24 and 31% increase in C(max) and AUC(0-infinity) of deramciclane, respectively, under fed condition is modest and probably has no clinical significance since it is relatively small compared to the inter-individual variability of these parameters.

In vitro simulation of food effect on dissolution of deramciclane film-coated tablets and correlation with in vivo data in healthy volunteers.

The in vitro dissolution profiles of deramciclane 30 mg film-coated tablets, an acid-labile new 5-HT receptor antagonist, were studied under simulated fasting and fed conditions. Artificial gastric juice with pH adjusted to that of fasting conditions was applied either alone or after adding different dietary components. The use of the USP dissolution apparatus II (paddle method) showed that the presence of dietary components has markedly affected the amount of unchanged drug dissolved. As a similar tendency had been observed in food-effect studies in healthy volunteers, cumulative area under the curve (AUC(cum)) for both fed and fasting conditions were compared and an in vitro--in vivo correlation (IVIVC) was evaluated. A linear relationship was established between logarithmic in vivo blood sampling time and in vitro dissolution time assigned to equal AUC(cum) ratios (AUC(cum, fed)/AUC(cum, fasting)). Despite its limitations, in vitro modelling of in vivo conditions might help provide a base for predicting in vivo drug behaviour.

Studies of the side chain cleavage of deramciclane in rats with radiolabelled compounds.

The pharmacokinetics of deramciclane and especially the fate of its side chain were studied in rats after oral treatment, using (3)H- and (14)C-labelled (ring- or side chain labelled) deramciclane and (14)C-dimethylamino-ethanol ((14)C-DMAE) radioisomers. The labelled compounds were admixed and the total radioactivities of both labels were simultaneously determined. The data obtained from the analysis of the plasma concentration-time curves revealed that an intensive cleavage (30-40%) of the side chain occurred at the ether bond. The core of deramciclane, carrying the ring label, was almost completely eliminated during 24 h, while the elimination of the side chain was very slow (t(1/2)(beta): 99 h). The side chain residue most probably represents dimethylamino-ethanol, but the presence of dimethylglycine (DMG) cannot be excluded. The AUC(0-infinity) and the MRT values of DMAE were found to be much higher than those of the parent compound. In addition to the plasma levels, the time related changes of the tissue concentrations of the radioisomers of deramciclane were analysed both in the brain and the hypophysis. The concentration-time curves have shown similar characteristics to those of the plasma, but higher concentrations were reached in both organs (the highest in the hypophysis). It is postulated that the low rate of formation and elimination of the metabolite(s) (DMAE or DMG) indicates that, due to their endogenous nature, they can be incorporated into choline/acetylcholine or protein synthesis.

Determination of deramciclane and N-desmethylderamciclane in human plasma by liquid chromatography-tandem mass spectrometry using off-line robotic sample pretreatment.

A rapid and highly sensitive LC-MS-MS method using deuterium-labelled internal standards was developed and evaluated for the simultaneous determination of deramciclane and its pharmacologically active metabolite (N-desmethylderamciclane). The sample preparation based on liquid-liquid extraction was carried out with an off-line robotic system. Evaluation of this analytical method shows that samples can be assayed with acceptable accuracy and precision in the 0.1 to 50 ng/ml concentration range for both compounds. The method was applied for the quantitative determination of deramciclane and its metabolite in human plasma samples during a food interaction pharmacokinetic study.

Oral, intraperitoneal and intravenous pharmacokinetics of deramciclane and its N-desmethyl metabolite in the rat.

The pharmacokinetic properties of deramciclane fumarate (EGIS-3886), a new potential anxiolitic agent, and its N-desmethyl metabolite have been investigated in Wistar rats after 10 mgkg(-1) deramciclane fumarate was administered orally, intraperitoneally or intravenously. A highly sensitive, validated and optimized gas chromatographic method with nitrogen selective detection (GC-NPD) using a solid-phase extraction technique was used to determine plasma levels of the parent compound and its N-desmethyl metabolite. After oral administration the absorption of the parent compound was very fast (t(max) 0.5h). The maximum plasma concentration (C(max)) was detected at 44.9, > or =177.8 and > or =2643.0 ngmL(-1) after oral, intraperitoneal and intravenous administration of deramciclane, respectively. For the metabolite the respective Cmax values were 32.0, > or =25.4 and 51.0 ngmL(-1). The pharmacokinetic curves of both the parent compound and its metabolite showed enterohepatic recirculation for all administration routes. The biological half-life (tbeta 1/2) for deramciclane ranged from 3.42 to 5.44 h and for the N-desmethyl metabolite the range was 2.90-5.44 h, after administration of the drug by the three different routes. After intravenous administration AUC0-infinity, of deramciclane was 29.2- and 5.4-times higher than that observed after oral and intraperitoneal treatment, respectively. These AUC0-infinity ratios were only 2.1- and 1.5-times higher for the metabolite. The absolute bioavailability of deramciclane in rats was 3.42% after oral and 18.49% after intraperitoneal administration. The comparative pharmacokinetic study of deramciclane in rat after the different administration routes showed fast absorption. Furthermore, plasma levels were found to be administration route-dependent, low bioavailability of the parent compound indicated an extremely fast and strong first-pass metabolism. The apparent volume of distribution suggested strong tissue binding after administration of the drug by any of the three routes studied.