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Y Q Lou

Publications and source records attributed to Y Q Lou.

At least 19 recordsLinked to original sources
PubMed1997

[Study of the molecular mechanism of human cytochrome P450 and genetic polymorphism of drug oxidative metabolizing enzyme].

Polymorphism has been detected in a variety of drug-metabolizing enzymes at both phenotypic and genotypic level. Human cytochrome P450 enzymes have been studied extensively in recent years, and the majority of mutations which give rise to a defective phenotype have now been identified(for example CYP2D6, CYP2C19, etc.). There are some groups of enzymes showing definite polymorphism at the phenotypic level but the exact genetic mechanisms are not yet clear(CYP1A1, CYP1A2, etc.). There are still other groups of enzymes, showing some indication of polymorphism at either the phenotypic or genotypic level yet have not been unambiguously demonstrated (for example CYP2A6, CYP2C9, CYP2E1, CYP3A4, etc.). The molecular mechanism of all these polymorphisms and possible polymorphisms is discussed, with particular reference to the effects of this variation on drug metabolism and on the susceptibility to chemically-induced diseases.

Cytochrome P-450 Enzyme System↗
PubMed1996

[Enzyme kinetic studies on the in vitro metabolism of omeprazole by Chinese human liver microsomes].

In the present study, a specific and reliable method was developed for the determination of omeprazole and its two major metabolites, hydroxyomeprazole (OH-OPZ) and omeprazole sulfone (OPZ-SFN) in Chinese adult human liver microsome by reversed phase HPLC assay. Formation of these metabolites is linear for at least 60 min and between 0.25 and 1 mg.ml-1 of microsomal protein. The enzyme kinetic analysis of the reaction revealed that the hydroxylation Vmax and K(m) obtained with the human liver microsomal preparation were 42.9 nmol.min-1.(mg protein)-1 and 6.49 mumol.L-1, respectively. The maximum formation rates of OPZ-SFN (Vmax) was 6.63 nmol.min-1.(mg protein)-1, with a K(m) value of 11.8 mumol.L-1. A number of compounds were tested for their ability to inhibit OPZ metabolism. Our results showed that mephenytoin, diazepam and nordiazepam are competitive inhibitors and papaverine is an uncompetitive inhibitor of OPZ hydroxylation. These studies suggest that the same isozyme metabolising MP, DZ and NDZ (may be P450 2C or P450 3A) may be involved in the hydroxylation of OPZ. Moreover, the compounds tested also have some effects on the formation of OPZ-SFN in vitro with Chinese human liver microsomes.

Adult↗
PubMed1995

[The molecular mechanism of polymorphism of S-mephenytoin hydroxylative metabolism].

The hydroxylation of S-mephenytoin exhibits a genetic polymorphism in humans and there are a large interethnic differences in the frequency of the poor metabolizer phenotype. A S-mephenytoin P450-hydroxylase termed P450 UK was purified and identified to be CYP 2C19 by amino-terminal amino acid analyses. The levels of P450 2C19 and the ability of the human liver samples to 4'-hydroxylate S-mephenytoin were found to be strongly correlative. Recent report showed that the principle defect in S-mephenytoin poor metabolizers is a single base pair (G-->A) mutation in exon 5 of CYP 2C19 resulting in an aberrantly spliced mRNA and a non-functional P450 2C19 protein in liver of S-mephenytoin PM. Further investigations demonstrate that this major defect is responsible for about 75% of poor metabolizer phenotype in both caucasians and orientals who are homozygous for S-mephenytoin hydroxylation defect. This genetic defect (CYP 2C19) also affects metabolism of several other widely clinical used drugs.

Aryl Hydrocarbon Hydroxylases↗
PubMed1995

[In vitro studies on omeprazole metabolism in rat liver microsomes].

The metabolism of omeprazole to its two major metabolites, hydroxyomeprazole (OH-OPZ) and omeprazole sulfone (OPZ-SFN) was studied in rat liver microsomes by a reversed phase HPLC assay. The formation of metabolites of OPZ depended on incubation time, substrate concentration, microsomal protein concentration, and was found to be optimal at pH 7.4. The Vmax and Km of OPZ hydroxylation in the rat liver microsomal preparation were 2033 nmol/(min.mg protein) and 46.8 mumol.L-1 respectively. The maximum rate of formation of OPZ-SFN (Vmax) was 187.9 nmol/(min.mg protein), with a Km value of 120.7 mumol.L-1 in rat liver microsome. Moreover, the effects of 7 drugs on OPZ metabolism were tested. The results showed that mephenytoin, benzodiazepines (DZ, NDZ, TMZ, FNZ, NZ) and papaverine caused inhibition of OPZ metabolism, among them papaverine was the only fairly strong inhibitor.

Animals↗
PubMed1995

[Methodological study on the determination of naftopidil concentration in biological samples by HPLC].

A method was developed for the determination of the novel antihypertensive drug naftopidil in biological samples by HPLC. Metoprolol was used as the internal standard. The analytical column was a stainless steel column filled with 10 micron C18 packing. The mobile phase was a mixture of methanol-acetonitrile-water-0.2 mol.L-1 HAc-0.2 mol.L-1 NaAc (50:45:5:0.9:0.1). Detection was performed at UV 232 nm. Biological samples can be well purified after two extractions with ether. The lowest detection limit was 5 ng.ml-1. The precision and accuracy within-day and day-to-day ranged from 3.17 to 10.88%. The mean recoveries were 79.35% to 95.72%. The results showed that this method was simple, sensitive and good enough to be used in pharmacokinetic study of naftopidil.

Animals↗
PubMed1994

[Methodological study on the determination of oxiracetam concentration in serum and urine by HPLC].

A method was developed for the determination of oxiracetam concentration in serum and urine by HPLC. Acyclovir was used as an internal standard. The analytical column was a stainless-steel column (30 mm x 4.6 mm ID) filled with 10 microns Bondapak NH2. A mixture of acetonitrile and water (80: 20) as mobile phase was used at a flow rate of 1 ml.min-1. Detection was performed at 210 nm. The retention times were 6.3 min for oxiracetam and 8.1 min for the internal standard. The lower detection limits were 1 microgram.ml-1 for serum and 20 micrograms.ml-1 for urine. The precision and accuracy within-day and day-to-day for both serum and urine samples ranged from 5.0 to 10.7%. The mean recoveries were 99.7 +/- 5.9% and 99.0 +/- 5.6% for human serum and urine, respectively. The results showed that the method is simple, rapid, sensitive, reliable and good enough to be used in studying the clinical pharmacokinetics of oxiracetam.

Chromatography, High Pressure Liquid↗
PubMed1993

[A chiral capillary gas chromatographic method for direct determination of enantiomers of mephenytoin in human urine].

A gas chromatographic method equipped with nitrogen-phosphorus detector was developed for the determination of the S- and R-enantiomers of the anticonvulsant, mephenytoin (MP) in human urine. Dichloromethane (4 ml) was added to 1 ml urine, the mixture was shaken and centrifuged. The organic phase was transferred to another tube and blown to dryness under nitrogen on water bath (37 degrees C). The residue was dissolved in 10 microliters ethylacetate and 1-2 microliters was injected into the GC. Our results showed that direct enantiomeric separation of mephenytoin was obtained by using a chiral capillary column, the retention times for S- and R-mephenytoin were 25.5 and 26.2 min respectively, with a detection limit less than 50 ng/ml of mephenytoin. Similar linear and reproducible standard curves were obtained over the concentration range of 53.2 to 2128.0 ng/ml (for S-MP, r = 0.9914 +/- 0.0070, n = 6; and for R-MP, r = 0.9939 +/- 0.0070, n = 6), and the mean recoveries of S- and R-MP were 95.4% and 95.8% respectively. The within-day relative standard deviations were less than 8.8% for both S- and R-MP, and that of between-days were less than 14.3%. There was a good reproducibility of the urine S/R mephenytoin determined in China and in Sweden by using similar method in 107 Chinese volunteers after a single oral dose of 100 mg racemic mephenytoin (r = 0.9091, P < 0.001).

Chromatography, Gas↗
PubMed1992

Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin.

The frequency of poor metabolizers of debrisoquin was low and similar in four different native Chinese nationalities. In a total sample of 695 Chinese subjects, only seven (1.01%) had a urinary ratio between debrisoquin and 4-hydroxydebrisoquin greater than 12.6, which is the antimode between poor metabolizers and extensive metabolizers in white populations. This is significantly lower than the 6.82% found in 1011 white Swedish healthy subjects (p less than 0.0001). Admixture analysis indicated the occurrence of two distributions within extensive metabolizers among both Chinese and white subjects. The mean of the distribution of metabolic ratios among Chinese extensive metabolizers was shifted toward higher values compared with Swedish extensive metabolizers (p less than 0.01). The frequency of poor metabolizers of S-mephenytoin was higher in 137 Chinese (14.6%) than in 488 Swedish (3.3%) subjects (p less than 0.0001). Our findings imply that drugs metabolized by these two polymorphic hydroxylases should be prescribed in different dosages to Chinese and white subjects.

China↗
PubMed1991

[Study on the frequency distribution of debrisoquine hydroxylation deficiency in Chinese healthy Zang and Wei volunteers].

The metabolic ratio of debrisoquine hydroxylation (MR) determined as the ratio of debrisoquine over 4-OH-debrisoquine in 8 h urine after a single oral dose of DB (10 mg) in unrelated Chinese Zang and Wei volunteers was studied by using gas chromatography. The MR of 132 healthy Chinese Zang subjects ranged from 0.20 to 34.32, and that of 158 healthy Chinese Wei subjects ranged from 0.13 to 29.73. Two phenotypes were apparent in the frequency distribution histograms with an antimode at log MR = 1.10 (MR = 12.6). Two subjects were therefore identified as poor metabolizers (PMs) of DB in 132 Zang volunteers (the frequency of PMs was found to be 1.52%), and only one in 158 Wei volunteers (0.63%). Neither sex nor smoking habit affected the DB hydroxylation (P greater than 0.2). The recoveries of DB and 4-OH-DB in Zang volunteers were 19.83 +/- 10.99 and 11.57 +/- 7.04%, and in Wei volunteers they were 22.74 +/- 14.41 and 17.77 +/- 10.82%, respectively.

Adolescent↗
PubMed1990

Diazepam metabolism in native Chinese poor and extensive hydroxylators of S-mephenytoin: interethnic differences in comparison with white subjects.

A single oral 5 mg dose of diazepam was given to 16 healthy native Chinese Han volunteers. Eight volunteers were extensive metabolizers of S-mephenytoin, and eight were poor metabolizers of S-mephenytoin. Plasma levels of diazepam and its demethyl metabolite were determined by HPLC in blood samples drawn during 4 weeks. There was no difference in diazepam disposition between the two phenotypes. However, the plasma half-life of demethyldiazepam was longer in poor metabolizers than in extensive metabolizers of mephenytoin (mean +/- SD: 161 +/- 37 and 116 +/- 29 hours, respectively; p less than 0.02). The plasma concentrations of demethyldiazepam at 7, 14, and 21 days after intake of diazepam were significantly higher in poor metabolizers than in extensive metabolizers. We compared the pharmacokinetic parameters of diazepam in Chinese subjects with our previously reported data from white subjects. The mean plasma half-life values of diazepam in Chinese extensive metabolizers (85.1 hours) and poor metabolizers (88.3 hours) were very similar to those in white subjects who were poor metabolizers (88.3 hours), and more than twice those in white subjects who were extensive metabolizers (40.8 hours). In parallel, the mean clearance of diazepam in Chinese subjects (independent of phenotype) was similar to that in white subjects who were poor metabolizers, but half that in white subjects who were extensive metabolizers. Chinese subjects had a slightly larger volume of distribution of diazepam than white subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1990

Polymorphism of debrisoquine 4-hydroxylation and family studies of poor metabolizers in Chinese population.

Debrisoquine hydroxylation capacity determined as the ratio of debrisoquine over 4-OH-debrisoquine in 8-h urine after a single dose (10 mg) was studied in 140 unrelated Chinese Han subjects and 2 families of poor metabolizers (PM) of debrisoquine. In the 140 Chinese subjects the frequency of PM was found to be 1.43% (2/140), much lower than the 5-10% in white population reported. No sex difference was shown on the hydroxylation of debrisoquine. The recoveries of debrisoquin, 4-OH-debrisoquine in 8-h urine were 16 +/- 11 and 13 +/- 6%, respectively. None of the parents in the 2 families was PMs. Phenotype distribution in each family and population was consistent with the hypothesis that debrisoquine 4-OH-hydroxylation activity is under diallelic, monogenetic control, with the PM phenotype inheriting in an autosomal recessive trait.

Adolescent↗
PubMed1989

[HPLC determination of tetramethylpyrazine in human serum and its pharmacokinetic parameters].

An HPLC method for the determination of tetramethylpyrazine in serum and application of this method to tetramethylpyrazine deposition studies in human body were described. Tetramethylpyrazine was extracted from alkalinized serum with dichloromethane using methaqualone as internal standard. A RP mu-Bondapak-C18 (10 microns) column fitted with a variable-wavelength UV spectrophotometer operated at 280 nm was used. The mobile phase was methanol-water (58:42). The detection limit of the method was 0.0174 microgram/ml serum. Assay linearity was shown over the range of 0.0291-5.816 micrograms/ml serum with a regression coefficient of 0.9999. The extraction recovery was 99.84% and no interference was found from endogenous compounds, metabolites of parent drug or other commonly used drugs. For the serum concentration following oral administration of tetramethylpyrazine capsules to healthy volunteers (n = 6), the best fit was found to be with a two compartment open model. After administration of 174.5 mg dose, the pharmacokinetic parameters were as follows: Tp = 0.5102 h, Cmax = 3.114 micrograms/ml, AUC = 5.893 mg/L.h, T1/2 (Ka) = 0.1508 h, T1/2 (alpha) = 0.4855 h, T1/2 (beta) = 2.894 h, C1 = 15.7 L.h-1, Vc = 17.70 L, V = 66.77 L. The results imply that tetramethylpyrazine is absorbed rapidly, distributed widely in the body, and also eliminated at a fairly rapid rate.

Administration, Oral↗
PubMed1989

[Studies on the metabolism of antiepilepserine in isolated perfused rat liver].

The metabolism of antiepilepserine, 3,4-methylene dioxycinnamyl piperidine, was studied in isolated perfused rat liver. Two metabolites were separated and purified by means of HPLC. They were identified as 3,4-methylene dioxycinnamyl hydroxypiperidine and 4-hydroxy-3-methoxycinnamyl piperidine by UV and MS. The latter was further confirmed by chemical synthesis. The pharmacokinetics of antiepilepserine in isolated perfused liver was also studied. Parameters obtained include a first order elimination constant, k = 0.0157 +/- 0.0043 min-1, and a half-life, t 1/2 = 46.7 +/- 11.9 min, (n = 6). The amount of antiepilepserine lost during the perfusion could not be compensated by the increased amount of metabolites. Antiepilepserine was found to be tightly bound and stored in the liver. This might be one of the explanations of the first pass effect of antiepilepserine after oral administration.

Animals↗
PubMed1989

[Calcium antagonism of enpiperate on isolated rabbit aorta strips and guinea pig ileum].

Enpiperate, 4-(3, 5)-exocydopropyl-N-methylpiperidyl diphenyl hydroxy acetate, was synthesized in China. It has been shown to have no effect on the normal tension of rabbit aorta strips or contractions induced by NE. It inhibited the contraction of high K+-depolarized rabbit aorta strips at concentrations of 3.8 and 10.9 mumol/L. The same effect was seen on isolated guinea pig ileum, at a concentration of 10.9 mumol/L, which was depolarized by Ca2+ free high K+ Locke-Ringer's solution and the contraction was extragenous Ca2+ dependent. The inhibition was overcome by increasing the extracellular Ca2+ concentration. In the presence of EDTA (0.1 mmol/L), the NE induced intracellular Ca2+ dependent contraction was inhibited by enpiperate (3.8, 10.9 mumol/L), although no significant difference was found between enpiperate and papaverine. It is suggested that enpiperate is a calcium antagonist and that the antagonism is carried out by blocking the potential dependent calcium channel (PDC) in the membrane of vascular smooth muscles. A intracellular calcium antagonistic action may also be involved.

Animals↗