The absorption, distribution, excretion, and metabolism of a single oral dose of O-ethyl O-4-nitrophenyl phenylphosphonothioate in hens

The disposition and metabolism of a single oral 10 mg/kg (LD50) of uniformly phenyl-labeled [14C]EPN (O-ethyl O-4-nitrophenyl [14C]phenylphosphonothioate) were studied in adult hens. The birds were protected from acute toxicity with atropine sulfate. Three treated hens were killed at each time interval (days): 0.5, 2, 4, 8, 12. Radioactivity was adsorbed from the gastrointestinal tract and distributed in all tissues. Most of the dose was excreted in the combined urinary-fecal excreta (74%). Only traces of the radioactivity (0.2%) were detected in expired CO2. Most of the excreted radioactive materials were identified as phenylphosphonic acid (PPA), O-ethyl phenylphosphonic acid (EPPA), and O-ethyl phenylphosphonothioc acid (EPPTA). Radioactivity in tissues reached a peak of 11.8% in 12 days. The highest concentration of radioactivity was present in the liver followed by bile, kidney, adipose tissue, and muscle. EPN was the major compound identified in brain, spinal cord, sciatic nerve, kidney, and plasma. Most of the radioactivity in the liver was identified as EPPA followed by EPPTA and PPA. Kinetic studies showed that EPN disappeared exponentially from tissues. The half-life of the elimination of EPN from plasma was 16.5 days corresponding to a constant rate value of 0.04 day-1. Relative residence (RR) of EPN relative to plasma was shortest in liver and longest in adipose tissue followed by sciatic nerve and spinal cord.     

Disposition,elimination and metabolism of O-ethylO-4-nitrophenyl phenylphosphonothioate after subchronic dermal application in male cats

The metabolism, distribution, and excretion of the insecticide O-ethylO-4-nitrophenyl phenylphosphonothioate (EPN) were studied in the male cat. Each cat was given a daily dermal dose of 0.5 mg/kg [¹⁴C] EPN for 10 consecutive days. Fifteen days after the last dose, the cats had excreted 62% of the cumulative dose in the urine and 10% in the faces. No ¹⁴CO₂ was detected in the expired air. O-Ethyl phenylphosphonic acid (EPPA) was identified as the major urinary and fecal metabolite. Phenylphosphonic acid (PPA) was the second highest metabolite. Only traces of the intact EPN were recovered in the urine and feces. The disposition studies performed 1, 5, 10 and 15 days after the administration of the last dose showed that EPN was the major compound identified in the brain, spinal cord, sciatic nerve, adipose tissue, plasma and kidney. Most of the radioactivity in the liver was identified as EPPA followed by PPA. The time course of plasma EPN, determined after the 10th daily dose was biphasic. The slower process had a half-life of 17.0 days. After tissue distribution was completed, tissue elimination was adequately represented as a single first-order process.     

Metabolism and pharmacokinetics of a single oral dose of O-4-bromo-2,5-dichlorophenyl O-methyl phenylphosphonothioate (Leptophos) in hens

The metabolism and pharmacokinetics of a subneurotoxic dose of leptophos were determined in laying hens following a single oral dose of 50 mg/kg (0.9 μCi/hen) of [phenyl¹⁴C]leptophos (O-4-bromo-2,5-dichlorophenyl O-methyl [¹⁴C]phenylphosphonothioate). This study adds confirmatory evidence to the hypothesis that species selectivity for delayed neurotoxicity is related to interspecies differences in pharmacokinetics and metabolism. Oral leptophos was metabolized and excreted slowly in hens. The major portion of the radioactivity (86.5%) was excreted during the 20-day experiment. Significant amounts of the dose were deposited in egg albumen and yolk—3.4 and 2.5%, respectively. Only 1.3% was excreted in expired CO₂. Radioactivity in tissues reached a peak of 14.6% of the dose 12 hr after administration; radioactivity decreased to 6.2% after 20 days (42.6% of peak value). The highest ¹⁴C concentration was present in the bile, followed by the gall bladder, kidney, adipose tissue, and liver. Brain, spinal cord, and sciatic nerve, which are affected by the neurotoxicity of leptophos, had smaller but constant concentrations throughout the experiment. Following the oral administration of [¹⁴C]leptophos the change in the ¹⁴C body burden with time was biexponential. The physiological disposition of leptophos may therefore be defined in terms of a two-compartment open-system model. Radioactivity was excreted at a slow rate, β value of 0.05 day^?1, corresponding to a half-life of 12.0 days. Leptophos was the only compound identified in nerve tissues, muscle, fat, and blood. Most of the radioactive substances in the excreta and liver were identified as unchanged leptophos with minor amounts of polar metabolites. The metabolic fate of leptophos can be explained on the basis of its physical properties of lipid solubility and tissue binding, and the predominant biliary secretion and gastrointestinal excretion of the compound.     

Potential of neurotoxicity after a single oral dose of 4-bromo-, 4-chloro-, 4-fluoro- or 4-iodoaniline in rats

The potential for neurotoxicity after a single oral dose of four halogenated aniline derivatives--4-bromoaniline (4-BA), 4-chloroaniline (4-CA), 4- fluoroaniline (4-FA) and 4-iodoaniline (4-IA)--was given to rats was investigated at or near the lethal dosage level. Hindlimb paralysis was found in the 4-BA, 4-CA and 4-FA groups on clinical observation, with the maximum incidence of 100% in the 4-BA and 4-FA groups and 66.7% in the 4-CA group. Detailed clinical observations with functional tests identified the following effects: reduced response of hindlimb extensor thrust, gait abnormality in the open field and decreased grip strength in the fore- or hindlimbs in the 4-BA, 4-CA and 4-FA groups; decreased number of supported rearing episodes in the open field in the 4-BA and 4-CA groups; abnormal landing in the aerial righting reflex in the 4-BA and 4-FA groups; and prolonged surface righting reflex in the 4-BA group. Spongy change in the white matter of the spinal cord and brainstem and nerve fibre degeneration in the peripheral nerves were found in all haloaniline-treated groups. The central and peripheral nervous systems were most severely affected in the 4-BA group and the lesions in the 4-IA group were limited in grade. This study demonstrates that a bolus dose of 4-haloanilines to rats induces a neurotoxicity similar in character to that evoked by the parent aniline. The decreasing order of neurotoxic potential appears to be 4-BA > 4-FA > or = 4-CA > 4-IA when comparing at or near the lethal dosage level.     

Pharmacokinetics and metabolism of a topically applied dose of O-4-bromo-2,5-dichlorophenyl O-methyl phenylphosphonothioate in hens.

Investigations into the pharmacokinetics and metabolism of a topically applied 50 mg/kg dose of ¹⁴C-labeled leptophos (O-4-bromo-2,5-dichlorophenyl O-methyl [¹⁴C]phenylphosphonothioate) on the comb of hens are reported. A total of 35.4% of the applied dose was absorbed through the skin during the 20-day experiment. Combined urinary-fecal excreta accounted for most of the radioactivity (24.3% of the applied dose). Significant amounts of the dose were deposited in egg albumen and yolk: 2.5 and 2.0%, respectively. Only 1.3% was excreted in expired CO₂. Radioactivity in tissues reached a peak of 17.1% of the dose 12 hr after administration; radioactivity decreased to 5.0% after 20 days (29.4% of peak value). Highest ¹⁴C content was present in the muscle, followed by the skin, adipose tissue, and the liver. Central and peripheral nerve tissues were shown throughout the experiment to contain small constant amounts of ¹⁴C. The change in the ¹⁴C in the body with time showed a biphasic pattern. The half-life for the elimination of ¹⁴C from the bird's body was 17.0 days corresponding to a rate value β of 0.04 day^?1. Most of the radioactive substances in the excreta and liver were identified as unchanged leptophos with minor amounts of polar metabolites. The fate of leptophos was rationalized on the basis of its physical properties, i.e., lipid solubility and tissue binding, and predominant biliary secretion and gastrointestinal excretion.     

Plasma levels after a single oral dose of proscillaridin

Summary Plasma levels of proscillaridin, measured by a modified⁸⁶Rb-erythrocyte method, have been studied in 6 healthy volunteers who received single oral doses of 2.5 mg. There were two maxima in the plasma curve, one after 0.5 h (median level 410 pg/ml) and another after 10 h (median value 390 pg/ml); and, a distinct minimum at 3 h (median value 98 pg/ml). After 24 h the median plasma concentration was 305 pg/ml, and after 48 h it was 115 pg/ml.     

Disposition of monodesethylamodiaquine after a single oral dose of amodiaquine and three regimens for prophylaxis againstPlasmodium falciparum malaria

Summary The disposition of monodesethylamodiaquine was studied in four healthy subjects after a single oral dose of 10 mg/kg amodiaquine base.Amodiaquine was not found in any sample, but the major metabolite monodesethylamodiaquine was detected and was assumed to be the sole derivative that contributed significantly to antimalarial activity in the blood. The best fit for the decay of the metabolite was obtained with a three-compartment model. The half-lives of the first two phases were 3.2 to 11.4 h for t_1/21 and 22.7 to 50.3 h for t_1/22 in plasma. The half-life of the terminal phase ( t_1/2) was between 9 and 18.2 days. The concentration in whole blood was 4- to 6-times higher than in plasma.Three schedules (alternate days, weekly, daily) of the conventional prophylactic dose of 10 mg/kg per week were compared in six other healthy subjects. There were significant differences in the plasma monodesethylamodiaquine levels between the three schedules.The work was presented in part at the 34th Meeting of the American Society of Tropical Medicine and Hygiene, Miami, Florida (4–7 November 1985)     

Excretion of digoxin and its metabolites in urine after a single oral dose in healthy subjects

The 3-day urinary excretion of digoxin, its conjugated and unconjugated hydrolytic metabolites and dihydrodigoxin, was studied in 8 healthy men after oral administration of tritiated digoxin. Analysis was performed by high pressure liquid chromatography (HPLC). The total radioactivity corresponded to 45.4±2.0 per cent (mean ± S.E.M.) of the dose. By HPLC 424 ± 2.7 per cent was recovered before and 44.0 ± 2.7 per cent after deconjugation of the samples. Digoxin and dihydrodigoxin constituted 40.3 ± 2.9 per cent; of this 0.7 ± 0.4 per cent was dihydrodigoxin. The sum of the hydrolytic metabolites was 2.1 ± 0.3 per cent before and 3.4± 0.5 per cent after deconjugation. No correlation was found between gastric pH and the production of hydrolytic metabolites. The relative amount of these metabolites was maximal (mean 13.4 per cent of the excretion) in the 4.8 h sampling period. During the first 8 h an average of 8.6 per cent of the radioactivity was not recovered by HPLC. The metabolism of digoxin as judged by urinary excretion was limited and showed great variation during the early hours after treatment. The excretion of unchanged digoxin in some individuals constituted as little as 60 per cent over the first 12 h after dosing.     

单次口服阿奇霉素片在中国健康志愿者的药代动力学

目的研究阿奇霉素(大环内酯类抗生素)在中国健康人体的药代动力学。方法 10名健康志愿者单剂量口服阿奇霉素500 mg后,高效液相色谱-紫外检测法测定血清药物浓度;用AIC法结合F检验判别房室模型, DAS程序计算药代动力学参数。结果主要的药代动力学参数:Ka为(0．87 ±0．27)h-1,t1／2β为(39．66±10．85)h,tmax为(2．60±0．52)h,Cmax为(451．19 ±67．72)μg·L-1,CL／F为(0．56±0．13)L·(h·kg)-1,AUC0-144和 AUC0-∞分别为(13．68±2．92)mg·h·L-1和(13．71±2．91)mg·h·L-1。结论最佳房室模型为二室模型。     

氚化赖氨酸一次灌胃后氚在大鼠体内的滞留与代谢

Wistar 大鼠一次经口灌入氚化赖氨酸,在灌入氚后的不同时间测定分析了主要组织器官中总氚(湿组织中的氚)和结合氚(干组织中的氚)的活度,并根据组织中的氚活度估算了氚至组织的剂量率。实验结果表明,氚在组织中的活度随氚灌入后时间的延长按指数下降规律逐步降低,其分布不很均匀。肾和肝中的氚活度高于血和睾丸,而睾丸最低。氚灌入后第15天时在组织中的滞留活度约占第一天的 9 ％左右。组织剂量率的排列范围为肝10×10~(-8)～2.0×10~(-8);肾11×10~(-8)～1.9×10~(-8);血6.0×10~(-8)～1.6×10~(-8);睾丸3.7×10~(-6)～1.2×10~(-8)。从剂量率的估算结果看,随氚摄入后时间增加剂量率逐渐降低,第10天时最低。     

Inter- and intra-individual variation in the metabolism of methaqualone in man after a single oral dose

Summary The urinary excretion of fiveC-monohydroxy metabolites and theN-oxide metabolite of methaqualone in the 24h period immediately after oral dosing with 250 mg methaqualone (Melsed) has been measured in nineteen healthy adults (13 male, 6 female) to assess interindividual variations and in five adults (3 male, 2 female) on five separate occasions to assess intraindividual variations. The overall importance of the six metabolites was 4-hydroxy > $$ " align="middle" border="0"> N-oxide > $$ " align="middle" border="0"> 2-hydroxymethyl > 3-hydroxy > 6-hydroxy = 2-hydroxymethyl. Variations in this order both within the 24h period and within each of the three eight-hour periods constituting the 24 hours were minor and variations in the absolute amount of each metabolite excreted ranged from two to three-fold. Intraindividual variations were generally smaller than interindividual variations and for each individual the pattern of metabolism was similar on the five occasions. There is evidence that theC-oxidation of methaqualone may be more sensitive to cyclical variations in hormone levels than isN-oxidation.     

Chemical characterization of ASTA Z 7557 (INN mafosfamide,CIS-4-sulfoethylthio-cyclophosphamide), a stable derivative of 4-hydroxy-cyclophosphamide

Summary The primary metabolite of cyclophosphamide (CP, 1), i.e. 4-hydroxy-CP 2, has high pharmacological activity, but it is a very unstable compound. Chemical approaches to the stabilization involved in the substitution of the hydroxy group at the C 4-position, especially by a sulfoalkylthio-moiety. Within this new class of compounds ASTA Z 7557 (2-(bis-(2-chloroethyl))-amino-cis-4-((2-sulfoethyl)-thio)-tetrahydro-2H-1,3,2-oxazaphosphorine-r-2-oxide cyclohexylamine salt, i.e. cis-4-sulfoethylthio-CP, cis-13) was chosen for further evaluation. Cis-13 was synthesized by condensation of compound 2 and 2-mercapto-ethanesulfonic acid cyclohexylamine salt 14 in aqueous acetone yielding the cis-isomer with high stereoselectivity. It is a white crystalline powder, m.p. 126–134°C, stable at room temperature, with a solubility of 16% in water. The stereochemistry was confirmed by NMR-data and X-ray diffraction. In 0.07 M phosphate buffer at pH 7 and 37°C cis-13 isomerizes to the epimer trans-13, equilibrating at a cis-trans-ratio of 59 to 41 within less than 5 minutes. Simultaneously a rapid initial hydrolysis occurs to 2 and 14 followed by a time period with lower degradation due to the decomposition of 2. The rate of release of 2 increases with decreasing concentration and especially by addition of an oxidant. It could be retarded by addition of the corresponding thiol mesna, sodium 2-mercapto-ethanesulfonate 15, or of another thiol. In the presence of 3-mercapto-propane sulfonate 13 yielded 4-(3-sulfopropyl)thio-CP17.With changing pH values from 2 to 9, the lowest hydrolytic speed was observed at pH 4.0 to 4.3. For clinical use cis-13 is prepared as a lyophilisate containing additional sodium citrate buffer to guarantee this optimal pH value.     

Proteomic analysis and the antimetastatic effect ofN-(4-methyl)phenyl-O-(4-methoxy) phenyl-thionocarbamate-induced apoptosis in human melanoma SK-MEL-28 cells

We employed human SK-MEL-28 cells as a model system to identify cellular proteins that accompany N-(4-methyl)phenyl-O-(4-methoxy)phenyl-thionocarbamate (MMTC)-induced apoptosis based on a proteomic approach. Cell viability tests revealed that SK-MEL-28 skin cancer cells underwent more cell death than normal HaCaT cells in a dose-dependent manner after treatment with MMTC. Two-dimensional electrophoresis in conjunction with matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry analysis or computer matching with a protein database further revealed that the MMTC-induced apoptosis is accompanied by increased levels of caspase-1, checkpoint suppressor-1, caspase-4, NF-kappaB inhibitor, AP-2, c-Jun-N-terminal kinase, melanoma inhibitor, granzyme K, G1/S specific cyclin D3, cystein rich protein, Ras-related protein Rab-37 or Ras-related protein Rab-13, and reduced levels of EMS (oncogene), ATP synthase, tyrosine-phosphatase, Cdc25c, 14-3-3 protein or specific structure of nuclear receptor. The migration suppressing effect of MMTC on SK-MEL-28 cell was tested. MMTC suppressed the metastasis of SK-MEL-8 cells. It was also identified that MMTC had little angiogenic effect because it did not suppress the proliferation of HUVEC cell line. These results suggest that MMTC is a novel chemotherapeutic and metastatic agents against the SK-MEL-28 human melanoma cell line.     

A pharmacokinetic and safety study of single dose intravenous combretastatin A4 phosphate in Chinese patients with refractory solid tumours

AIMS

This trial was conducted to evaluate the safety and pharmacokinetics of combretastatin A4 phosphate (CA4P) given intravenously as a single dose to Chinese patients with refractory solid tumours.

METHODS

Twenty-five patients were treated with single doses of CA4P according to a dose escalation scheme: 5, 10, 20, 33, 50, 65 and 85 mg m⁻² infused intravenously over 30 min.

RESULTS

CA4P was generally well tolerated at ≤65 mg m⁻². Transient, moderate increases in the heart rate-corrected QT interval occurred at all doses. CA4P produced a transient dose-dependent increase in neural and gastrointestinal toxicities. Acute renal failure occurred in one dehydrated patient who had also taken paracetamol. There were seven episodes of dose-limiting toxicity at doses ≥65 mg m⁻², including two episodes of reversible ataxia at 85 mg m⁻². For CA4P, at 50 mg m⁻², mean (SD) peak plasma concentration (C_max) was 0.99 (0.33) µm, area under the curve from time zero to time of last quantifiable concentration (AUC(0,t)) was 1.42 (0.30) µm h and terminal elimination half-life (t_1/2) was 1.81 (0.61) h. At 65 mg m⁻², C_max was 1.73 (0.62) µm, AUC(0,t) was 3.19 (1.47) µm h and t_1/2 was 1.90 (0.61) h. One patient with nasopharyngeal carcinoma had an obvious clinical response with central necrosis in the metastatic lung mass.

CONCLUSION

Doses ≤65 mg m⁻² given as 30 min infusions define the maximum tolerated dose in East Asian patients, and doses in the range of 50–65 mg m⁻² have been selected for further studies.     

Elimination rate ofN-acetylprocainamide after a single intravenous dose of procainamide hydrochloride in man

Equations were derived which made it possible to determine the elimination rate of N -acetylprocainamide from urinary data after intravenous administration of procainamide hydrochloride. A single dose of 500 mg of the drug was infused intravenously in four healthy subjects. On the basis of those equations, the formation rate of the metabolite could be calculated presuming that all rate processes were occurring by first-order processes. However, close examination of the excretion rate data appears to support the contention that the formation or excretion of N -acetylprocainamide may be occurring by a saturable process.     

Absolute bioavailability and metabolism of omeprazole in relation to CYP2C19 genotypes following single intravenous and oral administrations

Objective The aim of this study was to evaluate the absolute bioavailability and the metabolism of omeprazole following single intravenous and oral administrations to healthy subjects in relation to CYP2C19 genotypes. Methods Twenty subjects, of whom 6 were homozygous extensive metabolizers (hmEMs), 8 were heterozygous EMs (htEMs) and 6 were poor metabolizers (PMs) for CYP2C19, were enrolled in this study. Each subject received either a single omeprazole 20 mg intravenous dose (IV) or 40 mg oral dose (PO) in a randomized fashion during 2 different phases. Results Mean omeprazole AUC (0,∞) was 1164, 3093 and 10511 ng h/mL after PO, and 1435, 2495 and 6222 ng h/mL after IV in hmEMs, htEMs and PMs, respectively. Therefore, the absolute bioavailability of omeprazole in PMs was significantly higher than that in hmEMs (p < 0.001) and htEMs (p < 0.001). Hydroxylation metabolic indexes after IV and PO were significantly lower in PMs than in hmEMs (p < 0.001) and htEMs (p < 0.001), and was correlated with the absolute bioavailability (p < 0.0001 for both IV and PO). Sulfoxidation metabolic index after IV was significantly different between the CYP2C19 genotypes, whereas no difference was found after a single oral dose. Conclusion This study indicates that the absolute bioavailability of omeprazole differs among the three different CYP2C19 genotypes after a single dose of omeprazole orally or intravenously. Hydroxylation metabolic index of omeprazole may be mainly attributable to the genotype of CYP2C19. As for the sulfoxidation metabolic index after a single oral dose, intestinal CYP3A may be contributed to omeprazole metabolism.     

Pharmacokinetics and metabolism of a single subneurotoxic oral dose of tri-o-cresyl phosphate in hens

Hens were given a single oral dose of 50 mg (4.6 Ci)/kg [¹⁴C] tri-o-cresyl phosphate (TOCP). Four groups of three hens each were killed after 0.5, 1, 2, and 5 days. The half-life of¹⁴C in plasma was 2 days. TOCP and its metabolites in the plasma, liver, kidneys, and lungs were analyzed by high-performance liquid chromatography and liquid scintillation counting. TOCP reached its highest concentration in plasma between 0.5 and 1 day after administration. Under these experimental conditions, the disappearance of TOCP from the plasma followed monoexponential kinetics with a half-life of 2.2 days. Appreciable concentrations of saligenin cyclic-o-tolyl phosphate, the active neurotoxic metabolite, were detected in the plasma as well as in the liver, kidneys, and lungs at all time points and had half-lives of 2.06, 1.36, 1.11 and 4.44 days, respectively. The presence of this active metabolite of TOCP might contribute to the sensitivity of the hen to TOCP-induced delayed neurotoxicity. Other hydrolytic and oxidative products of TOCP were also identified in tissues.     

含L-4-氧代赖氨酸和N3-(4-甲氧基富马酰)-L-2,3-二氨基丙酸寡肽类似物的合成及其抗白念珠菌活性

运用“违法传递”概念,根据白念珠菌对寡肽的传送特点,设计并合成了8个含L-4-氧代赖氨酸(以下称I-677)和N³-(4-甲氧基富马酰)-L-2,3-二氨基丙酸(以下称FMDP)的寡肽类似物,均系新化合物。体外抗白念珠菌试验表明:I-677-FMDP-肽(I-677-FMDP,I-677-AA-FMDP,其中AA=Nva,Val,Leu,Phe,Pro,D,L-p-Cl- Phe,D-Pgly)是I-677单体摩尔活性的40～770倍,是FMDP的60～1130倍,其摩尔最低抑菌浓度为6.56×10^-9～3.5×10^-10mol·disk^-1。羧肽酶A存在时化合物I-677-FMDP体外抗菌试验表明,含FMDP的化合物I-677-FMDP能抵抗羧肽酶A的酶解。     

Distribution and metabolism of gastrodin in rat brain

Gastrodin is the major and bioactive component in Tianma (Gastrodia elata Bl.) and has sedative, anticonvulsive and neuroprotective effects. Since little is known about its neuropharmacokinetics and brain metabolism, this study was undertaken to investigate the kinetic inter-relationship of gastrodin in rat plasma, cerebrospinal fluid (CSF) and brain microdialysate (frontal cortex, hippocampus, thalamus and cerebellum). Gastrodin was administered via the femoral vein at a dose of 200mg/kg, and blood, CSF and brain microdialysate were collected at timed intervals for the measurement of gastrodin concentrations by high-performance liquid chromatography. The samples were analyzed on a Diamonsil C18 column (5 microm, 250 mm x 4.6mm i.d.) with a mobile phase consisting of acetonitrile-water (5% acetonitrile for brain microdialysate, 2.5% acetonitrile for plasma and CSF), and detected with a UV detector at 221 nm. The distribution of gastrodin in rat showed that levels of gastrodin declined rapidly after drug administration, and the entry of gastrodin into the brain was rapid. However, the ratios of AUC(brain)/AUC(plasma) were not high. The individual ratios of the AUC in the CSF, frontal cortex, hippocampus, thalamus and cerebellum to the AUC in the plasma were 4.8+/-2.4%, 3.3+/-1.2%, 3.0+/-0.7%, 3.3+/-1.3% and 6.1+/-1.9%, respectively. The AUC in the cerebellum was significantly higher than that in other brain regions (P<0.05). The concentrations of p-hydroxybenzyl alcohol, the main metabolite of gastrodin, were very low both in the CSF and plasma.