Biomedical subjects

S Zeng

Publications and source records attributed to S Zeng.

At least 19 recordsLinked to original sources

PubMed2006

Low molecular weight polyethylenimines linked by beta-cyclodextrin for gene transfer into the nervous system.

BACKGROUND: Polyethylenimines (PEIs) with high molecular weights are effective nonviral gene delivery vectors. However, the in vivo use of these PEIs can be hampered by their cellular toxicity. In the present study we developed and tested a new PEI polymer synthesized by linking less toxic, low molecular weight (MW) PEIs with a commonly used, biocompatible drug carrier, beta-cyclodextrin (CyD). METHODS AND RESULTS: The terminal CyD hydroxyl groups were activated by 1,1'-carbonyldiimidazole. Each activated CyD then linked two branched PEI molecules with MW of 600 Da to form a CyD-containing polymer with MW of 61 kDa, in which CyD served as a part of the backbone. The PEI-CyD polymer developed was soluble in water and biodegradable. In cell viability assays with sensitive neurons, the polymer performed similarly to low-MW PEIs and displayed much lower cellular cytotoxicity compared to PEI 25 kDa. The gene delivery efficiency of the polymer was comparable to, and at higher polymer/DNA ratios even higher than, that offered by PEI 25 kDa in neural cells. Attractively, intrathecal injection of plasmid DNA complexed by the polymer into the rat spinal cord provided levels of gene expression close to that offered by PEI 25 kDa. CONCLUSIONS: The polymer reported in the current study displayed improved biocompatibility over non-degradable PEI 25 kDa and mediated gene transfection in cultured neurons and in the central nervous system effectively. The new polymer would be worth exploring further as an in vivo delivery system of therapeutic genetic materials for gene therapy of neurological disorders.

Animals↗

PubMed2006

Novel self-aggregates of chitosan oligosaccharide grafted stearic acid: preparation, characterization and protein association.

A novel hydrophobically modified chitosan oligosaccharide (CSO) containing 5.4 stearic acid (SA) groups per 100 anhydroglucose units was synthesized by an 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)-mediated coupling reaction. The purified copolymer was structurally characterized by IR spectroscopy. Characteristics of self-aggregates of the amphiphilic copolymers were studied by fluorescence spectroscopy and dynamic light scattering. The critical aggregation concentration (cac) value of the self-aggregates in aqueous solution was determined by measuring the fluorescence intensity of pyrene as a fluorescent probe. Mean diameter of self-aggregates in pH 7.0 PBS was 25.0 +/- 14.7 nm with a unimodal size distribution. The diameter, as well as the zeta potential of self-aggregates increased when the pH value of dispersion medium decreased. Bovine serum albumin (BSA) was further enveloped in the interface of different single self-aggregate and formed nanoparticles. The size of BSA-loaded stearic acid modified CSO nanoparticles depended on the pH values of the dispersed aqueous vehicle, and the size diminished when the pH values of the dispersed aqueous vehicle decreased, whilst, the BSA encapsulation efficiency enhanced. The nanoparticles were characterized by Transmission Electron Microscopy (TEM). BSA release from stearic acid modified CSO nanoparticles decreased when the pH values of the delivery media decreased, in the range from 7.2 to 5.8.

Chitosan↗

PubMed2006

Zolmitriptan uptake by human intestinal epithelial Caco-2 cells.

The oral uptake of zolmitriptan, a novel and highly selectively 5-HT 1B/1D receptor agonist, was evaluated in the human epithelial cell line caco-2 that possesses intestinal enterocyte-like properties when cultured in vitro. The study demonstrated that zolmitriptan uptake significantly depended upon the extracelluar temperature and pH in the Caco-2 cell. The zolmitriptan uptake at 39 degrees C was 2.1 fold as that at 23 degrees C and the zolmitriptan uptake at pH 8.0 was 2.7 fold as that at pH 6.0. The uptake rates of zolmitriptan on both sides increased with increasing zolmitriptan concentration from 0.1 to 10 mmol x L(-1), and it shows concave concentration-dependency at high concentration. The uptake rates of zolmitriptan on the basolateral side (BL) were 3-7 times higher than that on the apical side (AP). Verapamil, nimodipine, nifedipine, flunarizine, amiloride and sumatriptan significantly increased the uptake rates of zolmitriptan on the apical sides. Propafenone significantly inhibited the uptake rate of zolmitriptan on both sides. Propranolol and aspirin have no significant effect. The results indicated that the zolmitriptan uptake in Caco-2 cells was temperature, pH and concentration dependent, and was partially counteracted by the action of an outwardly directed efflux pump, presumably p-glycoprotein. Absorption interactions should be considered when P-gp substrates or inhibitors, Na+ -H+ exchange inhibitors, P-gp ATPase agonists or inhibitors are co-administered with zomitriptan in clinical practice.

Absorption↗

PubMed2005

Controlled release of levonorgestrel from biodegradable poly(D,L-lactide-co-glycolide) microspheres: in vitro and in vivo studies.

Poly(D,L-lactide-co-glycolide) (PLG) biodegradable microspheres containing a contraceptive drug, levonorgestrel (LNG), were prepared using both the solvent evaporation method and a modified solvent extraction-evaporation method. The microspheres prepared with the solvent evaporation process had porous surfaces with low product yields and poor encapsulation efficiencies. On the other hand, the microspheres prepared using the modified solvent extraction-evaporation method were nonporous with encapsulation efficiencies close to 100%. In vitro drug release showed the nonporous microspheres had a lower initial burst and a slightly prolonged duration of release than those porous microspheres. In vivo release kinetics of the low burst microspheres were determined by measuring LNG plasma levels after a single intramuscular injection to female rats. At a LNG dose of 41.1 mg/kg, average plasma LNG levels were 6-10 ng/ml in the first 24 h and subsequently remained above 1 ng/ml until 126 days. The duration above the minimum effective LNG plasma level of 0.2 ng/ml was 168 days. By comparison, a similar dose of LNG microcrystals used as control produced a much higher plasma level of 15-21 ng/ml in the first day followed by a fast and continuous decline of LNG levels with a duration of only about 35 days.

Animals↗

PubMed2005

Stereoselectivity and interaction between the glucuronidation of S-(-)- and R-(+)-propranolol in rat hepatic microsomes pretreated with different inducers.

Phase II glucuronidation metabolism of side-chain propranolol was studied using microsomes from rats treated with the inducers beta-naphthoflavone (BNF) or dexamethasone (Dex). The glucuronide concentrations of propranolol enantiomers were assayed by RP-HPLC. The kinetic constants of glucuronidation, Km, Vmax and Clint were determined. There are significant differences between the R- and S-enantiomeric glucuronide in Km, Vmax and Clint P < 0.05, P < 0.01 and P < 0.05 in control microsome. There are significant differences in Km and Clint (P < 0.01 or P < 0.001) but no significant differences in Vmax (P > 0.05) between R and S-enantiomeric glucuronide in the microsomes induced with Dex and BNF. The formation of S-(-)-propranolol glucuronide was inhibited by R-(+)-propranolol from the rat microsomes pretreated with BNF and Dex. The glucuronidation metabolism of propranolol enantiomers exhibited the stereoselectivity in rat hepatic microsomes induced with BNF or Dex. Multiple UGT1A and 2B may be involved in stereoselective O-glucuronidation of propranolol enantiomers in rat liver microsomes. The glucuronides produced were in favor of the R-enantiomer. There is an interaction between the glucuronidation of R- and S-enantiomer.

Adrenergic beta-Antagonists↗

PubMed2005

Analysis of luteolin in Elsholtzia blanda Benth. by RP-HPLC.

The total luteolin content in Elsholtzia blanda Benth. extracts (EBBE) was determined using reversed phase HPLC. C18 was used as the packing material and 0.01 M phosphate buffer (pH 2)-tetrahydrofuran-isopropanol (70:30:5) as the mobile phase with detection wavelength 360 nm. The recovery of the method was 96.4%-101.8%, and the assay was linear at concentrations from 5 to 200 microg/ml (r = 0.9999). The results indicated that the content of luteolin in EBBE extracted under different conditions varied significantly. This method can be used to optimize the extraction procedure and determine the content of luteolin in Elsholtzia blanda Benth. extracts.

Chromatography, High Pressure Liquid↗

PubMed2003

Determination of quercetin and kaempferol in human urine after orally administrated tablet of ginkgo biloba extract by HPLC.

A sensitive, simple and accurate method was developed for determination of quercetin and kaempferol in human urine by reversed phase high performance liquid chromatography. The urine samples were analyzed on C18 column. Quercetin and kaempferol were analyzed simultaneously with good separation. UV detector was set at 380 nm. There was a linear relationship between chromatographic area of analytes and concentration of analytes over the concentration range 1.638-81.90 and 1.872-93.60 ng/ml for quercetin and kaempferol, respectively. The recovery of the assay was 99.7+/-6.2 and 97.4+/-7.2% for quercetin and kaempferol, respectively. The within-day and between-day coefficients of variation were less than 9.7 and 16.5% (RSD), respectively. The limit of detection was 1.0 ng/ml for quercetin and 1.1 ng/ml for kaempferol. The limit of quantitation was 1.61+/-0.11 ng/ml (n=5) for quercetin and 1.85+/-0.11 ng/ml (n=5) for kaempferol. The method developed has been applied to determine quercetin and kaempferol after orally administrated tablet of Ginkgo biloba extract in human urine.

Calibration↗

PubMed2003

Determination of dextromethorphan and its metabolite dextrorphan in human urine by capillary gas chromatography without derivatization.

A sensitive, simple and accurate method was developed for determination of dextromethorphan (DM) and dextrorphan (DT) in human urine by capillary gas chromatography without derivatization. After an oral dose of 30 mg DM, urine samples were collected and extracted, then analyzed on 0.22 mmx17 m HP-1 capillary column. DM and its metabolite DT were analyzed simultaneously with good separation. Docosane was used as the internal standard (I.S.). The detector used was flame ionization detector (FID). There was a linear relationship between peak area ratios of analytes to I.S. and concentration of analytes over the concentration range 0.37-7.38 micromol/l for DM and 0.39-77.8 micromol/l for DT. The recovery was 88.1 approximately 103.9% for DM and 86.7 approximately 96.8% for DT. The within-day and between-day coefficients of variation were less than 7.4 and 7.3% (RSD) for the assay of DM and DT in urine, respectively. The limits of detection (LOD) were 0.30 micromol/l for DM and 0.16 micromol/l for DT. The limits of quantitation (LOQ) were 0.37 micromol/l (RSD<6%) for DM and 0.39 micromol/l (RSD<7%) for DT. The method has been applied to determine the oxidative phenotypes of cytochrome P450 2D6 (CYP2D6) in a Chinese population with metabolic ratio of DM in human urine.

Adolescent↗

PubMed2003

Milk and milk components reduce the motility of Ostertagia circumcincta larvae in vitro.

AIM: To examine the effects in vitro of bovine milk and milk products and soymilk on the motility of sheathed and exsheathed L3 Ostertagia circumcincta (also known as Teladorsagia circumcincta) as a measure of larval viability and infectivity. METHODS: L3 were exsheathed in 0.2% sodium hypochlorite, resuspended in Hank's Balanced Salt Solution (HBSS) pH 7.4 and incubated with test solutions at 37 degrees C for up to 48 h. The motility of 50 larvae from each incubate was assessed at selected times using a McMaster slide. Larvae were considered immotile only if straight and not moving. Fresh bovine milk, homogenised milk (3.3% fat), low-fat milk (0.2% fat) and lamb milk replacer were diluted with HBSS pH 7.4 to concentrations from 1.6-100%, and incubated with exsheathed L3 for 1, 24 or 48 h. Bovine whey protein was tested in concentrations of 5-15% at pH 2.5-6.5, casein at 5 or 7.5%, and skim milk powder from 5-15% at pH 5.5 or 6.5, all for 2, 4 or 24 h. Soymilk was tested in concentrations of 1.6-100% for 1, 2, 24 or 48 h. HBSS was used as the control solution. Sheathed L3 were incubated in HBSS pH 7.4, 50% homogenised milk in HBSS, or 50% soymilk in HBSS. Each solution was incubated for 1,2, 24 or 48 h. RESULTS: The motility of exsheathed L3 was reduced by fresh bovine milk, homogenised milk, low-fat milk, lamb milk replacer, whey, casein and skim milk solutions, but not by soymilk. The mean percentage (and SE) immotile at 48 h were: fresh milk 38% (SE 20); homogenised milk 65% (SE 7); low-fat milk 57% (SE 5); lamb milk replacer 43% (SE 7); and soymilk 7% (SE 0.5). Larval immotility increased in whey protein solutions from 5-15%, from pH 2.5-6.5 and from 2 to 24 h (all p<0.001); in skim milk from 5-15% (p<0.001), and was greater at pH 6.5 than at pH 5.5 (p<0.001); in casein from 5-7.5% (p<0.001), but was no different at pH 5.5 and 6.5. The motility of sheathed L3 was reduced at 24 h (p=0.009) and 48 h (p<0.001) by 50% homogenised milk, but not by 50% soymilk or HBSS. CONCLUSIONS: Bovine milk proteins, or components associated with the proteins, reduced the motility of both sheathed and exsheathed L3 O. circumcincta. Soymilk had no effect on nematode motility. Lower larval motility may reduce worm establishment and be a contributing factor to the smaller burdens of gastrointestinal nematodes in milk-fed animals compared with animals after weaning.

Journal Article↗

PubMed2003

Concentration dependent stereoselectivity of propafenone N-depropylation metabolism with human hepatic recombinant CYP1A2.

Concentration dependency of stereoselective N-depropylation metabolism of propafenone was studied by using transgenic cell line expressing human CYP1A2. Enantiomers of propafenone and N-depropylpropafenone were separated and assayed simultaneously by RP-HPLC with precolumn GITC chiral derivatization. The experimental results showed that CYP1A2 was involved in enantioselective N-depropylation of propafenone and that the metabolic stereoselectivity depends on substrate concentration. For racemic propafenone, stereoselectivity was observed at low substrate concentration and was not seen at high substrate concentration. For individual isomers, S-(+)-propafenone was metabolized faster than its antipode at higher enantiomer concentrations and R-(-)-propafenone was eliminated faster than its antipode at lower enantiomer concentrations. There is interaction between S- and R-propafenone. R-(-)-propafenone inhibited the metabolism of S-(+)-propafenone with IC50 0.225 mmol/L for human CYP1A2.

Anti-Arrhythmia Agents↗

PubMed2002

Chiral reversed phase high-performance liquid chromatography for determining propranolol enantiomers in transgenic Chinese hamster CHL cell lines expressing human cytochrome P450.

An enantioselective assay for S-(-)- and R-(+)-propranolol in transgenic Chinese hamster CHL cell lines, expressing human cytochrome P450 (CYP), was developed. The method involves extraction of propranolol from the S(9) incubates, using S-(+)-propafenone as internal standard, chiral derivatization with 2,3,4,6-tetra-O-beta-D-glucopranosyl isothiocyanate and quantitation by reversed phase high-performance liquid chromatography system with UV detection (lambda=220 nm). A baseline separation of propranolol enantiomers was achieved on a 5-microm reverse-phase ODS column, with a mixture of methanol/water/glacial acetic acid (67:33:0.05, v/v) as mobile phase. The assay is linear from 5 to 500 microM for each enantiomer. The analytical method affords average recoveries of 99.2% and 98.8% for S-(-)- and R-(+)-propranolol, respectively. The limit of quantitation for the method is 5 microM for both S-(-)- and R-(+)-propranolol. The reproducibility of the assay is satisfactory (RSD < 10%). The method allowed study of the depletion of S-(-)- and R-(+)-propranolol in transgenic Chinese hamster CHL cell lines expressing CYP3A4, CYP2C18 and CYP2C9.

Animals↗

PubMed2001

Phenotype analysis of cytochrome P450 2C19 in Chinese subjects with mephenytoin S/R enantiomeric ratio in urine measured by chiral GC.

A chiral gas chromatographic method with FID was developed for the determination of S- and R-mephenytoin in human urine. The assay is linear from 25 to 800 ng/mL for each enantiomer and the limit of detection and limit of quantitation were 12 and 25ng/mL for each enantiomer, respectively. The method affords average recoveries of 74.41 +/- 3.93% and 73.78 +/- 3.02% for S- and R-mephenytoin, respectively. The method allows the phenotype study of CYP2C19 in Chinese subjects. The phenotype pattern of 90 Chinese volunteers was determined, in which 26 volunteers received phenotyping and genotyping tests. The results of phenotype analysis showed that the interindividual variation was marked. The mephenytoin S/R enantiomeric ratios in urine of 11 volunteers were > or = 0.95 and identified as poor metabolizers. The frequency of poor metabolizers was 12.2% in the Chinese subjects tested. A good relationship between phenotype and genotype analysis of CYP2C19 was observed.

Aryl Hydrocarbon Hydroxylases↗

PubMed2001

Stereoselective determination of p-hydroxyphenyl-phenylhydantoin enantiomers in rat liver microsomal incubates by reversed-phase high-performance liquid chromatography using beta-cyclodextrin as chiral mobile phase additives.

An analytical method was developed for determination of p-hydroxyphenylphenylhydantoin enantiomers in rat liver microsome by using reversed-phase high-performance liquid chromatography. A 50 mm C(8) column was used as the analytical column. The mobile phase was made up of 8.8 mmol/L beta-cyclodextrin, 0.25 mol/L urea and 0.05 mol/L ammonium acetate in water. The assay was linear from 2.05 to 410.0 micromol/L for each enantiomer. The limits of detection and of quantitation for the method were 0.90 and 2.05 micromol/L for each enantiomer, respectively. The analytical method afforded average recoveries of 93.59 +/- 2.75% and 94.72 +/- 1.78% for S- and R-p-hydroxyphenylphenylhydantoin, respectively. The method allowed study of the in vitro glucuronidation of p-hydroxyphenylphenylhydantoin in rat liver microsomal incubates. The stereoselectivity of p-hydroxyphenylphenylhydantoin phase II metabolism was observed.

Animals↗

PubMed2001

The anti-proliferative effect of inhibitor of telomerase on cultured retinal pigment epithelial cells.

In order to provide a new method for treating proliferative vitreoretinopathy (PVR), the effects of anti-proliferation and apoptosis induction of inhibitors of telomerase and heat shock protein 90 (Hsp90) on the cultured retinal pigment epithelial (RPE) cells were investigated. The rate of apoptosis cells was measured by using TUNEL on the cultured RPE cells, the co-cultured RPE cells with inhibitor of telomerase (camptothecin) or the co-cultured RPE cells with inhibitor of Hsp90 (geldanamycin). The cell proliferation status was measured in the above three groups by using MTT method. The rate of apoptosis in the RPE cells co-cultured with camptothecin or geldanamycin was increased remarkably (P < 0.05). MTT showed the rate of growth inhibition was 8.4%, 32.3% and 72.3% at the concentrations of camptothecin 1 mumol/L, 5 mumol/L, 10 mumol/L, respectively, and 6.5%, 30.9%, 71.9% at the concentrations of geldanamycin 1 mumol/L, 5 mumol/L, 10 mumol/L, respectively. It was concluded that telomerase and Hsp90 can promote the proliferation of the cultured RPE cells, while the inhibitor of them can induce apoptosis and inhibit the growth of the RPE cells.

Apoptosis↗

PubMed2001

Highly toxic and broad-spectrum insecticidal Bacillus thuringiensis engineered by using the transposon Tn917 and protoplast fusion.

The chromosome of the Bacillus thuringiensis strain S184 that was toxic against the third instar larvae of Spodoptera litura with the LC(50) of 9.74 microg/ml was successfully integrated into two genes of cyt1Aa and cry11Aa using the transposon Tn917, yielding the primary engineered strain TnX. The strain TnX was highly toxic to the third instar larvae of Culex pipiens fatigans with the LC(50) of 5.12 ng/ml which was 1.82-fold higher than that of B. thuringiensis subsp. israelensis, but lowly toxic to lepidopterous larvae. By the protoplast fusion of the strain TnX and the strain S184-Tet(r) (resistance to tetracycline), the target engineered strain TnY was obtained. Against the third instar larvae of S. litura, the strain TnY LC(50) was of 4.68 micro g/ml and increased by 2.08-fold in comparison with the parent strain S184. Against the third instar larvae of C. pipiens fatigans, the strain TnY LC(50) was of 103.20 ng/ml. The two target genes of cyt1Aa and cry11Aa integrated into the chromosome were extremely stable and had little possibility of a second transposition. It was unclear whether some factors existing in the parent strain, S184, contributed to the high toxicity of the strains TnX and TnY.

Animals↗

PubMed2001

Immobilisation on polystyrene of diazirine derivatives of mono- and disaccharides: biological activities of modified surfaces.

The potential of surface glycoengineering for biomaterials and biosensors originates from the importance of carbohydrate-protein interactions in biological systems. The strategy employed here utilises carbene generated by illumination of diazirine to achieve covalent bonding of carbohydrates. Here, we describe the synthesis of an aryl diazirine containing a disaccharide (lactose). Surface analysis techniques [X-ray photoelectron spectroscopy (XPS) and time of flight secondary ion mass spectroscopy (ToF-SIMS)] demonstrate its successful surface immobilisation on polystyrene (PS). Results are compared to those previously obtained with an aryl diazirine containing a monosaccharide (galactose). The biological activity of galactose- or lactose-modified PS samples is studied using rat hepatocytes, Allo A lectin and solid-phase semi-synthesis with alpha-2,6-sialyltransferase. Allo A shows some binding to galactose-modified PS but none to lactose-modified surfaces. Similar results are obtained with rat hepatocytes. In contrast, sialylation of lactose-modified PS is achieved but not with galactose-modified surfaces. The different responses indicate that the biological activity depends not only on the carbohydrate per se but also on the structure and length of the spacer.

Animals↗

PubMed2001

Reduced Ostertagia circumcincta burdens in milk-fed lambs.

AIMS: To compare the susceptibility to parasitism by Ostertagia circumcincta of lambs fed entirely with bovine milk or weaned on to solid feed at 3 weeks of age. In addition, the effect of a single daily feed of milk on worm burdens was assessed. METHODS: Eight lambs were assigned to each of the 3 diets: milk (M), milk plus solid feed (cereal-based pellets and lucerne chaff) (MS), or solid feed only (S). Those to be fed solid feed were converted from complete milk feeding to the designated diet during their third week of life. From 3 weeks of age, all lambs were infected with 1000 O. circumcincta larvae twice weekly for 6 weeks; 4 lambs from each diet group were given normal sheathed L3 and another 4 were infected with exsheathed larvae. Faecal egg counts (FEC) and serum gastrin and pepsinogen concentrations were monitored from Day 17 after first infection, and worm burdens and abomasal pH and morphology were determined at necropsy. RESULTS: Total worm burdens and FEC were significantly lower in the M than MS and S groups, whereas there was no significant difference between those receiving sheathed and exsheathed larvae. The milk-fed lambs had a smaller reticulo-rumen and omasum and a more acidic abomasal pH. Serum gastrin and pepsinogen were increased in all groups, irrespective of diet or type of larvae used for infection. CONCLUSIONS: The cause of the lower worm establishment in lambs fed only milk was probably not failure to exsheath in the immature gastro-intestinal tract, as there were similar worm burdens in lambs whether sheathed or exsheathed larvae were administered. The lower pH of the abomasal contents of the preruminant lambs may have been a factor, as the parasites have previously been shown to die more rapidly in vitro at low pH. Alternatively, the milk itself had adverse effects on the parasites, but was ineffective when combined with solid feed. There was no benefit from feeding a milk plus solid diet over a solid diet.

Journal Article↗

PubMed2001

Chiral metabolism of propafenone in rat hepatic microsomes treated with two inducers.

AIM: To study the influence of inducers of drug metabolism enzyme, beta-naphthoflavone (BNF) and dexamethasone (DEX), on the stereoselective metabolism of propafenone in the rat hepatic microsomes. METHODS: Phase I metabolism of propafenone was studied using the microsomes induced by BNF and DEX and the non-induced microsome was used as the control. The enzymatic kinetics parameters of propafenone enantiomers were calculated by regress analysis of Eadie-Hofstee Plots. Propafenone enantiomer concentrations were assayed by a chiral HPLC. RESULTS: The metabolite of propafenone, N-desalkylpropafenone, was found after incubation of propafenone with the rat hepatic microsomes induced by BNF and DEX. In these two groups, the stereoselectivity favoring R(-) isomer was observed in metabolism at low substrate concentrations of racemic propafenone, but lost the stereoselectivity at high substrate concentrations. However, in control group, no stereoselectivity was observed. The enzyme kinetic parameters were: (1) K(m). CONTROL GROUP: R(-) 83+/-6, S(+) 94+/-7; BNF group: R(-) 105+/-6, S(+)128+/-14; DEX group: R(-) 86+/-11, S(+) 118+/-16; (2)V(max). CONTROL GROUP: R(-) 0.75+/-0.16, S(+) 0.72+/-0.07; BNF group: R(-) 1.04+/-0.15, S(+)1.07+/-14; DEX group: R(-) 0.93+/-0.06, S(+) 1.04+/-0.09; (3)Cl(int). CONTROL GROUP: R(-) 8.9+/-1.1, S(+) 7.6+/-0.7; BNF group: R(-) 9.9+/-0.9, S(+)8.3+/-0.7; DEX group: R(-) 10.9+/-0.8, S(+) 8.9+/-0.9. The enantiomeric differences in K(m) and Cl(int) were both significant, but not in V(max), in BNF and DEX group. Whereas enantiomeric differences in three parameters were all insignificant in control group. Furthermore, K(m) and V(max) were both significantly less than those in BNF or DEX group. In the rat liver microsome induced by DEX, nimodipine (NDP) decreased the stereoselectivity in propafenone metabolism at low substrate concentration. The inhibition of NDP on the metabolism of propafenone was stereoselective with R(-)-isomer being impaired more than S(+)-isomer. The inhibition constant (Ki) of S(+)- and R(-)-propafenone, calculated from Dixon plots, was 15.4 and 8.6 mg x L(-1), respectively. CONCLUSION: CYP1A subfamily(induced by BNF) and CYP3A4 (induced by DEX) have pronounced contribution to propafenone N-desalkylation which exhibited stereoselectivity depending on substrate concentration. The molecular base for this phenomenon is the stereoselectivity in affinity of substrate to the enzyme activity centers instead of at the catalyzing sites.

Animals↗