我国藏族与维吾尔族健康志愿者异喹呱羟化代谢缺陷频率的研究

本研究应用气相色谱法,测定了我国132位藏族和158位维吾尔族健康志愿者一次口服异喹胍(DB)10mg后8h尿中DB和4-羟异喹胍(4-OH-DB)的含量。结果表明,我国藏族和维族志愿者的DB羟化代谢均具双态性。求得藏及维族DB和4-OH-DB代谢比值的对数值(log MR)的范围分别为-0.70～1.54(MR为0.20～34.32)和-0.89～1.47(MR为0.13～29.73).以log MR=1.10为分界点,132位藏族和158位维族志愿者中分别有2个和1个弱代谢者。其缺陷频率分别为1.52和0.63%。吸烟和性别对DB羟化代谢的MR值无明显影响(P>0.2).服药后8h DB和4-OH-DB的回收率分别为:藏族19.83±10.99和10.81±6.58%;维族22.74±14.41和16.61±10.11%。     

中国壮族志愿者S—美芬妥英和异喹胍羟化代谢多态性研究

118名中国壮族（广西壮族自治区）志愿者一次口服消旋美芬妥黄100mg和异喹胍10mg后，应用气相色谱法分别测定尿中S－和R－美芬妥英含量比值和异喹胍及其代谢物4羟异喹胍含量比值，作为体内药物羟化代谢能力的指标，实验结果表明，118名志愿者中有12名的S／R美芬妥英比值大于1.0，是为S－美芬妥英弱羟化代谢者。说明我国壮族人群中S－美芬妥英羟化代谢缺陷频发率高达10.2%。但在118名壮族志愿者中未发现异喹胍弱羟化代谢者，且S－美芬妥英的羟化代谢多态发生态性和异喹胍羟化代谢多态性不存在着相关性，另外，选择其中16名志愿者（4名弱代谢者，12名强代谢者）研究了尿中美芬妥英和异喹胍及其代谢物的消除动力学规律，并估算了它们主要的药代动力学参数。     

中国壮族志愿者S─美芬妥英和异喹胍羟化代谢多态性研究

１１８名中国壮族（广西壮族自治区）志愿者一次口服消旋美芬妥英１００ｍｇ和异喹胍１０ｍｇ后，应用气相色谱法分别测定尿中Ｓ─和Ｒ─美芬妥英含量比值和异喹胍及其代谢物４羟异喹胍含量比值，作为体内药物羟化代谢能力的指标。实验结果表明，１１８名志愿者中有１２名的Ｓ／Ｒ美芬妥英比值大于１．０，是为Ｓ─美芬妥英弱羟化代谢者。说明我国壮族人群中Ｓ─美芬妥英羟化代谢缺陷频发率高达１０．２％。但在１１８名壮族志愿者中未发现异喹胍弱羟化代谢者，且Ｓ─美芬妥英的羟化代谢多态性和异喹胍羟化代谢多态性不存在着相关性。另外，选择其中１６名志愿者（４名弱代谢者，１２名强代谢者）研究了尿中美芬妥英和异喹胍及其代谢物的消除动力学规律。并估算了它们主要的药代动力学参数。     

中国健康志愿者普罗帕酮的药代动力学及与异喹胍,美芬…

应用高效液相色谱法及气相色谱法，研究了９名健康志愿口服单剂量普罗帕酮的药代动力学及与喹胍，Ｓ－美芬妥英羟化代谢多态性的相关性。结果表明，６名志愿中普罗帕酮按一房室模型消除，其余３名符合二房室模型，普罗帕酮消除半衰期半衰期３．４±ｓ１．１ｈ，药时曲线下面积为２．５±ｓ１．１μｇ．ｈ＾－＾１．ｍＬ＾－＾１，血浆清除率为１４５±ｓ６４Ｌ．ｈ＾－＾１。普罗帕酮药代动力学参数在异喹胍强与弱代谢中有较大     

中国健康志愿者普罗帕酮的药代动力学及与异喹胍，美芬妥英代谢多态性的相关性研究

应用高效液相色谱法及气相色谱法，研究了９名健康志愿者口服单剂量普罗帕酮的药代动力学及与异喹胍，Ｓ－美芬妥英羟化代谢多态性的相关性。结果表明，６名志愿者中普罗帕酮按一房室模型消除，其余３名符合二房室模型。普罗帕酮消除半衰期为３．４±ｓ１．１ｈ，药时曲线下面积为２．５±ｓ１．１μｇ·＝ｍＬ１，血浆清除率为１４５±ｓ６４Ｌ·ｈ１．普罗帕酮药代动力学参数在异喹胍强与弱代谢者中有较大的差异，而与Ｓ－美芬妥英不同羟化代谢表型则无明显相关性．同时服用普罗帕酮和异喹胍时，两药氧化代谢可产生互相抑制性影响．而普罗帕酮与Ｓ－美芬妥英公用则无明显改变，提示普鲁帕酮和异喹胍可能由同一肝微粒体细胞色素Ｐ４５０同工酶所催化代谢     

β-肾上腺素受体拮抗剂的多态氧化代谢及其临床药物动力学的探讨

药物的氧化代谢是对许多药物的效能、作用持续时间以及毒性的决定因素。这一高度可变过程受遗传、环境以及生理因素所控制。1977年发现抗高血压药异喹胍的主要代谢途径(4-羟化代谢)受多态型控制。有6～10%的白种人由于不能清除异喹胍故称之为乏代谢者(PoorMetabolizer,PMs);反之,大多数民族称为泛代谢者(Extensive Metabolizer,EMs)。受试者的表型是通过口服异喹胍10mg,收集8小时尿样,测量其中异喹胍与4-羟异喹胍之比     

汉族志愿者阿米替林代谢与异喹呱羟化代谢的关系

8名男性健康志愿者po阿米替林100 mg后,以阿米替林及其3种代谢物的血浓度曲线下面积(AUC₀^∞)计算阿米替林的脱甲基化代谢及羟基化代谢能力。结果提示个体间阿米替林及其3种代谢物的AUC差异很大。其中7名志愿者测定异喹呱羟化代谢表型,6例为异喹呱强代谢者,1例为弱代谢者。尿中异喹呱的羟化代谢率与阿米替林的羟基化代谢率、阿米替林和10-羟基阿米替林的AUC₀^∞呈显著相关。阿米替林总血浆清除率与异喹呱羟化代谢率呈弱相关。此结果表明阿米替林和异喹呱的羟化代谢可能由同一酶控制,阿米替林的羟基化代谢和脱甲基化代谢可能为两个独立的代谢途径。     

汉族志愿者阿米替林代谢与异喹呱羟化代谢的关系

8名男性健康志愿者po阿米替林100 mg后,以阿米替林及其3种代谢物的血浓度曲线下面积(AUC_0~∞)计算阿米替林的脱甲基化代谢及羟基化代谢能力。结果提示个体间阿米替林及其3种代谢物的AUC差异很大。其中7名志愿者测定异喹呱羟化代谢表型,6例为异喹呱强代谢者,1例为弱代谢者。尿中异喹呱的羟化代谢率与阿米替林的羟基化代谢率、阿米替林和10-羟基阿米替林的AUC_0~∞呈显著相关。阿米替林总血浆清除率与异喹呱羟化代谢率呈弱相关。此结果表明阿米替林和异喹呱的羟化代谢可能由同一酶控制,阿米替林的羟基化代谢和脱甲基化代谢可能为两个独立的代谢途径。     

恩卡胺和异喹胍多型代谢的遗传共同性

本文研究恩卡胺(encainide)与模型药异喹胍体内代谢的关系。随机选取健康受试者19人及2例需恩卡胺治疗的心律失常患者和患者之一的亲属4人。给予单剂量的盐酸恩卡胺和异喹胍,观察2天,两药间隔至少4天。测定血浆及尿中的O-脱甲基恩卡胺(ODE)、3-甲氧基-O-脱甲基恩卡胺(MODE)、N-脱甲基恩卡胺(NDE)和N、O-双脱甲基恩卡胺的浓度,以及尿中异喹胍和4-羟基异喹胍浓度。结果表明,恩卡胺消除速率     

应用中国成人肝微粒体研究地西泮代谢

本文建立了中国成人肝库，并应用中国成人肝微粒体研究了中国人地西泮代谢的规律和代谢地西泮的肝微粒体细胞色素Ｐ４５０氧化酶的特点，结果表明，中国人的地西泮代谢主要经Ｎ－去甲基化和Ｃ３－羟化反应，分别生成去甲地西泮（ＮＤＺ）和羟地西拌（ＴＭＺ）两种代谢产物，随着底物浓度的增加，这两种酶促反应呈双曲线分布，当底物浓度＞２０μｍｏｌ·Ｌ－１时，Ｎ－去甲基化反应的速率低于羟化反应速率，羟地西泮代谢物生成量明显高于去甲地西泮，同时发现，中国成人肝微粒体中可能存在着两种与地西泮具有不同亲和力的药酶组份，结果还表明，异喹胍，奎尼丁（被Ｐ４５０２Ｄ６酶所催化代谢）和美芬妥因，苯妥英（被Ｐ４５０２Ｃ类酶所催化代谢）对中国人肝微粒体试管内地西泮代谢无影响，而普奈洛尔及与Ｓ－美芬妥英羟化代谢相关的奥米拉唑能显著地抑制试管内地西泮的Ｎ－去甲基化和Ｃ３－羟化代谢反应。催眠药甲喹酮能显著地激活地西泮的氧化代谢反应。     

Pharmacogenetic covariation of defective N-oxidation of sparteine and 4-hydroxylation of debrisoquine

Summary Two subjects from each of the three groups of homozygous rapid, heterozygous, and homozygous non-metabolizers (N-oxidation) of sparteine received a single oral dose of debrisoquine. The urinary ratio of debrisoquine/4-hydroxy-debrisoquine, reflecting the individual's capacity to C-hydroxylate debrisoquine, was closely related to his phenotype for sparteine metabolism. This indicates that the two metabolic reactions are controlled by similar if not identical genetic factors.At Karolinska Institutet on temporary leave from Department of Angiology and Geriatrics, Medical School of Lübeck, Federal Republic of Germany.     

Involvement of CYP2D6 but not CYP2C19 in nicergoline metabolism in humans

1 Nicergoline, an ergot derivative previously used as a vasodilator, has gained a new indication in treating the symptoms of senile dementia.
2 Nicergoline is rapidly hydrolysed to an alcohol derivative, 1-methyl-10-α-methoxy-9,10-dihydrolysergol (MMDL), which is further N -demethylated to form 10-α-methoxy-9,10-dihydrolysergol (MDL). A few individuals display aberrant metabolism of this drug, as shown by their diminished capacity to form the MDL metabolite. The aim of this study was to determine whether defective nicergoline metabolism is associated with the debrisoquine and/or the S-mephenytoin hydroxylation polymorphisms.
3 After a single, oral 30  mg dose of nicergoline, the plasma concentrations of its two metabolites were studied in 15 subjects, divided into three groups with respect to their debrisoquine and S-mephenytoin hydroxylation phenotypes.
4 The pharmacokinetic parameters of MMDL and MDL were similar in the ten subjects who were extensive metabolisers of debrisoquine (five of whom were poor metabolisers of S-mephenytoin) (mean MMDL C _max 59  nmol l⁻¹ and AUC (0, t h) 144  nmol l⁻¹h, mean MDL C _max 183  nmol l⁻¹ and AUC 2627  nmol l⁻¹h) but were markedly different from the five subjects who were poor metabolisers of debrisoquine (mean MMDL C _max 356  nmol l⁻¹ and AUC 10512  nmol l⁻¹h, MDL concentrations below limit of quantitation).
5 We conclude that the formation of MDL from MMDL in the metabolism of nicergoline is catalysed to a major extent by CYP2D6 and that the observed interindividual variation in the metabolic pattern of the drug is related to the debrisoquine hydroxylation polymorphism.     

OXIDATION PHENOTYPING IN CHINESE AND MALAY POPULATIONS

1. Debrisoquine hydroxylation phenotyping was carried out in 97 Chinese and 97 Malay healthy volunteers. 2. No poor metabolizer was found in the Chinese population. Using a metabolic ratio antimode of 10.0, two poor metabolizers were present amongst the Malays studied.     

Debrisoquine oxidation polymorphism in a Tasmanian population

Summary The debrisoquine hydroxylation phenotype was studied in 152 unselected healthy Tasmanian subjects, who were mostly Caucasians of British ancestry. Following a 10 mg oral dose of debrisoquine (D), the ratio of D/4-hydroxydebrisoquine excreted in 8-h urine (metabolic ratio, MR) was determined.MR values were bimodally distributed. Thirteen subjects (8.6%) had MR values from 13.8 to 93.3 and were considered to be poor metabolisers of D, while the others were extensive metabolisers with MR values of 0.04 to 5.4. The D hydroxylation phenotype was not associated with sex.These findings confirm the constancy of D polymorphism in a Caucasian population even after migration to another country.     

The influence of cimetidine on debrisoquine 4-hydroxylation in extensive metabolizers

Summary We have studied the effect of cimetidine (800 mg·day^–1) administration for three days on debrisoquine 4-hydroxylation in nine healthy extensive metabolizers.The debrisoquine metabolic ratio was significantly increased (p<0.01), but the new ratios remained in the extensive metabolizer range (<12.6).These data suggest that pre-treatment with cimetidine in usual therapeutic doses will impair debrisoquine 4-hydroxylation, but not enough to alter the apparent oxidation phenotype.     

Metabolic oxidation of methaqualone in extensive and poor metabolisers of debrisoquine

Summary The metabolism of methaqualone to the glucuronides of 5 C-monohydroxy metabolites and to the N-oxide has been studied in 2 groups of healthy young adults phenotyped as extensive and poor metabolisers of debrisoquine. No significant interphenotype differences were observed with respect to the excretion of any of the 6 metabolites. It is probable that the genetic regulation of the pathways leading to these metabolites is at a locus other than that which is responsible for the regulation of the oxidation of debrisoquine, guanoxan, phenacetin, phenytoin and sparteine.     

The effect of codeine on gastrointestinal transit in extensive and poor metabolisers of debrisoquine

Methods: Codeine (50 mg) was administered to 12 extensive metabolisers (EM) and 12 poor metabolisers (PM) of debrisoquine. The oro-caecal transit time was estimated by the hydrogen breath test. The urinary excretion of codeine and metabolites during a 6-h interval was estimated after simultaneous analysis of codeine, morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), morphine (M), normorphine (NM), norcodeine, norcodeine glucuronide and codeine-6-glucuronide using HPLC. Results: The mean transit times after placebo were 1.3 h in the EM and 1.4 h in the PM. The corresponding figures after ingestion of codeine were 2.2 h and 2.1 h. The differences between the groups were statistically and clinically insignificant. The effect of codeine compared with placebo was significantly different in both groups. As expected, the metabolites of the O-demethylation pathway, M, M6G, M3G and NM were significantly lower in the PM. Interestingly, the recovery of the dose in the form of codeine (>1.7 times) and norcodeine (>2.5 times) was significantly higher in the PM, indicating compensatory metabolism via N-demethylation. Conclusion: In contrast to the analgesic effect, the prolongation of gastrointestinal transit caused by the drug does not depend on the formation of O-demethylated active metabolites M, M6G or NM. Received: 15 November 1996 / Accepted in revised form: 10 April 1997     

Lack of effect of chloroquine on the debrisoquine (CYP2D6) and S-mephenytoin (CYP2C19) hydroxylation phenotypes

The effects of chloroquine (CHQ) on debrisoquine hydroxylase (CYP2D6) and S-mephenytoin hydroxylase (CYP2C19) were assessed in 11 black Zimbabwean and 12 white Swedish healthy volunteers. The activity of CYP2D6 was measured as the urinary debrisoquine to 4-hydroxydebrisoquine metabolic ratio and that of CYP2C19 as the urinary S- to R-mephenytoin enantiomer ratio (S/R). There were no statistically significant differences in either metabolic ratio as a result of prophylactic or loading doses of CHQ. This indicates that CHQ does not inhibit CYP2D6 or CYP2C19 in vivo and is unlikely to compromise the metabolism of substrates for these two enzymes. It is, therefore, also unlikely that residual CHQ in populations under study will interfere with phenotyping of either CYP2D6 or CYP2C19.     

The influence of the sparteine/debrisoquine genetic polymorphism on the disposition of dexfenfluramine

1 To determine whether dexfenfluramine is a substrate of cytochrome P450 2D6 (CYP2D6), its disposition has been studied in nine extensive (EM) and eight poor metabolizers (PM) of debrisoquine. 2 Following a 30 mg dose of dexfenfluramine hydrochloride, urine was collected in all subjects for 96 h post-dose and plasma samples were collected in 11 subjects (six EMs and five PMs). Dexfenfluramine and nordexfenfluramine were measured in urine by h.p.l.c. and in plasma by g.c. 3 Urinary recovery of dexfenfluramine was greater in PMs than EMs (4136±1509 μg vs 1986±792 μg; 95% CI of difference 926–3374; P<0.05) whereas that of nordexfenfluramine was similar in both phenotypes (PM: 1753±411 μg vs 1626±444 μg). 4 Dexfenfluramine AUC was higher in PMs (677±348 μg l⁻¹ h) than EMs (359±250 μg l⁻¹ h). The apparent oral clearance of dexfenfluramine was greater in EMs than PMs (93.6±42.4 l h⁻¹vs 45.6±19.5 l h⁻¹; 95% CI of difference 1.2–94.7; P<0.05). The renal clearance was similar in both phenotypes (EMs: 5.88±2.83 l h⁻¹; PMs 6.60±2.01 l h⁻¹), indicating that the higher urinary recovery of dexfenfluramine in PMs reflects higher plasma concentrations, rather than phenotype differences in the renal handling, of dexfenfluramine. 5 The apparent nonrenal clearance of dexfenfluramine was substantially lower (P<0.05; 95% CI of difference 3.0–94.1) in PMs (39.0±19.5 l h⁻¹) than EMs (87.6±41.2 l h⁻¹). 6 There was a significant inverse correlation (r_s=−0.776 95% CI −0.31–−0.94; n=11; P=0.005) between the debrisoquine metabolic ratio and the apparent nonrenal clearance of dexfenfluramine. 7 PMs had a higher incidence of adverse effects (nausea and vomiting) than EMs. 8 In conclusion, the metabolism of dexfenfluramine is impaired in PMs. Thus CYP2D6, the isoenzyme deficient in poor metabolizers of debrisoquine, must catalyse at least one pathway of dexfenfluramine biotransformation.