The genetic polymorphism of sparteine metabolism

The formation of the two major metabolites of the antiarrhythmic and oxytocic drug sparteine (2- and 5-dehydrosparteine) exhibits a genetic polymorphism. Two phenotypes, extensive (EM) and poor metabolizers (PM) are observed in the population. The frequency of the PM phenotype in various populations (Caucasian and Japanese) ranges from 2.3 to 9%. The metabolism of sparteine is determined by two allelic genes at a single gene locus. PM subjects are homozygous for an autosomal recessive gene. The metabolism of sparteine is predominantly under genetic control as treatment with drugs such as antipyrine and rifampicin known to induce oxidative drug metabolism elicited only marginal changes in sparteine metabolism. The formation of 2-dehydrosparteine in human liver microsomes from EM and PM subjects showed a more than 40-fold difference in Km between EM and PM subjects. However, Vmax-values were almost identical in both groups. These data indicate that the basis of the differences in oxidative capacity between EM and PM subjects is more likely to be due to a variant isozyme with defective catalytic properties than to a decreased amount of the isozyme.     

Lack of evidence for polymorphism in metoprolol metabolism

The claim for polymorphism in the metabolism of metoprolol is based on a logical fallacy. A frequency distribution of metoprolol AUC data is presented and, although highly skewed, no evidence of more than a single population is apparent. Plasma and urine metoprolol and metabolite data are also presented to support this.     

Relevance of genetic polymorphism in drug metabolism in the development of new drugs

Summary Cuff blood pressure data has suggested that the calcium channel antagonist nisoldipine has full twenty four hour efficacy. To test this, 24 h ambulatory intra-arterial blood pressure monitoring was performed on 18 untreated hypertensive subjects (12 men, 6 women) (cuff blood pressure >150/95 mm Hg) before and after chronic treatment with 10–20 mg oral nisoldipine taken daily at 08.00 h. Twelve patients completed the study, six being withdrawn, four because of side-effects. After baseline intra-arterial monitoring patients were started on 10 mg nisoldipine daily. Response was assessed by cuff pressures taken 24 h after dosing at fortnightly intervals, and if not controlled (<150/95 or at least 10 mm Hg reduction in diastolic BP) the dose was increased to 20 mg. All patients received at least six weeks' therapy before the second intra-arterial blood pressure monitoring.There was a slight but insignificant reduction in mean daytime heart rate of 3 beats·min^–1. Mean significant reduction in daytime systolic and diastolic BP was 19 mm Hg and 13 mm Hg respectively but there was no significant mean night-time reduction. By comparison 8 out of 12 patients were apparently controlled more than 24 h post dose according to cuff pressures.This study suggests that this formulation of nisoldipine does not control blood pressure over a full 24-h period, and emphasises the importance of 24 h ambulatory monitoring in assessing the efficacy of once-daily antihypertensive agents.     

Extra-hepatic metabolism of midazolam.

Six patients received 10 mg of midazolam intravenously during the anhepatic period of liver transplantation. Arterial blood was sampled during this time and for a similar period following revascularisation. The plasma was analysed using gas chromatography and electron capture detection (GC-ECD) for midazolam alpha-hydroxymidazolam and alpha-hydroxymidazolam glucuronide. Five of the six patients had small but significant concentrations of metabolites detected during the anhepatic period, demonstrating the presence of extra-hepatic sites of metabolism for this drug. The remaining patient had plasma concentrations of metabolites below the lower limit of detection (2 micrograms l-1). This may represent a pharmacogenetic abnormality or a temporary failure of midazolam metabolism secondary to the patients illness affecting the extra-hepatic sites of metabolism.     

细胞色素P450基因多态性与药物代谢研究进展

细胞色素P450酶(cytochrome P450,CYP450)是参与人类药物代谢过程的重要酶,在肝细胞和小肠上皮细胞的光滑内质网中含量丰富,其主要功能是氧化还原各种内源性物质和外源性物质。CYP450酶参与80%目前应用药物的I相代谢,参与各种激素合成,影响与激素相关的肿瘤疾病发展。CYP450基因和表型存在高度多态性,体现在个体对于各种物质的代谢存在明显差异。本文综述了CYP450的基因多态性、与药物代谢相关的CYP450各亚型特点和临床意义,对发展以指导个体化用药为基础的精准医学具有重要意义。     

细胞色素P450氧化酶基因多态性对药物代谢影响的研究进展

细胞色素P450氧化酶是人体内的一种重要代谢酶,它能代谢和/或活化许多种药物、前致癌物、前毒物和致变剂。细胞色素P450氧化酶的基因具有遗传多态性,在人类存在等位基因的突变体。本文从基因结构、底物和影响其活性的因素、遗传多态性的分子机制等方面综述细胞色素P450氧化酶的研究进展。     

No evidence of intracellular oxidative stress during ischemia-reperfusion damage in rat liver in vivo.

The role of the intracellular generation of reactive oxygen species in the pathogenesis of ischemia-reperfusion damage of the liver was investigated in two in vivo rat models. Global hepatic ischemia was produced in the left and median lobes for 90 min followed by 60 min reperfusion to the total organ (model A) or only to the ischemic lobes (model B). Although both regimens caused significant rises in serum transaminases, this rise was higher in model B. In neither model was intracellular hydrogen peroxide production nor increased glutathione disulfide in bile found. The activities of various antioxidant enzymes were not affected by ischemia or ischemia-reperfusion. In conclusion, oxygen-free radicals are unlikely to be produced in the cells of rat liver during ischemia-reperfusion.     

Inhibitory effect of omeprazole on the metabolism of midazolam in vitro

To examine the effect of omeprazole on the hepatic drug metabolizing enzyme system microsomes from rat and human liver samples were incubated with midazolam (CAS 59467-70-8) in the absence and presence of various concentrations of omeprazole (CAS 73590-58-6), its sulfone metabolite and for comparison also with cimetidine. In the extracted incubation mixtures unchanged midazolam, a-OH-midazolam, 4-OH-midazolam and di-OH-midazolam were analyzed by HPLC. In both species omeprazole (and its sulfone) inhibited the formation of all three oxidized metabolites of midazolam and the corresponding IC50-values (range 0.2-1.3 mmol/l for rat microsomes and 0.2-1.5 mmol/l for human microsomes) were comparable to cimetidine (range 0.05 to 3.8 mmol/l). These results indicate that the oxidative metabolism of midazolam can be inhibited in vitro by omeprazole (and/or its sulfone metabolite) and this interaction should be considered if both drugs are administered concomitantly in man.     

Effects of heat exposure in a Finnish sauna on the pharmacokinetics and metabolism of midazolam

Objective: The effect of short-term heat exposure in a Finnish sauna on hepatic first-pass metabolism and the capacity to metabolize midazolam were studied in a crossover trial. Midazolam oral (15 mg) and intravenous (0.05 mg ⋅ kg⁻¹) was given to 6 healthy young male volunteers, in random order, during a control session and a sauna bathing session (temperature 85–100° C, relative humidity 25–30%). Blood samples for the determination of plasma midazolam and α-hydroxy midazolam concentrations were taken for 6 h after drug administration. Results: After oral administration, the bioavailability and clearance of midazolam were not affected by sauna bathing, nor was there a significant difference in α-hydroxy midazolam plasma concentration or the α-hydroxy midazolam/midazolam AUC-ratio between the sessions. Midazolam C_max was increased and its t_1/2β was prolonged during the sauna session, but the clinical relevance of the findings appears to be modest. The pharmacokinetics of intravenous midazolam were not affected by sauna bathing. Conclusions: Short-term heat exposure may not affect the first-pass metabolism or hepatic capacity to metabolize midazolam. Received: 23 October 1995 /Accepted in revised form: 22 May 1996     

Flavin-containing monooxygenase genetic polymorphism: impact on chemical metabolism and drug development

The flavin-containing monooxygenases (FMOs) metabolize a broad range of therapeutics. Consisting of five gene products in humans (FMO1-5), the different FMO family members exhibit pronounced tissue- and temporal-specific expression patterns. Substantial interindividual differences are also observed, and the inability to modulate with exogenous agents is consistent with an important role for genetic variation. Several rare FMO3 alleles causative for trimethylaminuria have been well characterized. However, the identification and characterization of functional FMO1-5 polymorphisms has been more recent. Although none of these polymorphisms has been associated with an adverse drug reaction, the continued broadening of our therapeutic armamentarium makes such an event likely in the future. Furthermore, at least one example has been reported for a direct association between FMO3 polymorphism and therapeutic efficacy. Thus, it is anticipated that knowledge regarding functionally-relevant FMO genetic variability will become increasingly important for making drug development and patient therapeutic choices.     

Pharmacokinetics and metabolism of oral midazolam in preterm infants

AIMS: To characterize the pharmacokinetics and metabolism of oral midazolam in 15 preterm infants. METHODS: After an oral dose (0.1 mg kg(-1)), blood was drawn up to 24 h after administration. Midazolam and 1-OH-midazolam concentrations were determined with GC-MS. In 8 out of these 15 patients the pharmacokinetics of intravenous midazolam was also studied. RESULTS: Apparent oral clearance, apparent volume of distribution, plasma half-life and 1-OH-Midazolam/Midazolam AUC ratio were [median (range)]: 2.7 [0.67-15.5] ml kg(-1) min(-1), 1.4 [0.3-12.1] l kg(-1), 7.6 [1.2-15.1], h and 0.03 [0.01-0.96], respectively. Absolute bioavailability was 0.49 [0.12-1.0]. CONCLUSIONS: Midazolam oral clearance is markedly decreased in preterm infants as compared with older children, probably because of immature CYP3A4 activity.     

Contribution of the genetic status of oxidative metabolism to variability in the plasma concentrations of beta-adrenoceptor blocking agents

Summary The oxidative metabolism of bufuralol is under the same genetic control as that of debrisoquine and sparteine. 154 fasting volunteers received a 30 mg tablet of bufuralol and a blood sample was taken 3 h later. In poor metabolizers (8% of the sample) the plasma bufuralol concentrations were very high and the metabolite concentrations were low. The genetic oxidative status is a major source of interindividual variation in the plasma concentration of drugs that undergo oxidative metabolism.Presented at the 50^th Annual Meeting of the Swiss Society of Internal Medicine, Lausanne, May 1982, and at the 8^th European Workshop on Drug Metabolism, Liège, September 1982     

Polymorphic oxidative metabolism of proguanil in a Nigerian population

OBJECTIVE: The genetic polymorphic metabolic oxidation of proguanil was investigated in 126 healthy, unrelated Nigerian subjects as an indication of the phenotypic status of CYP2C19 in Nigerians. METHODS: The proguanil oxidation capacity was determined using the 8-h urinary metabolic ratio of the parent drug and its metabolite (cycloguanil) after a single oral dose of 200 mg proguanil. RESULTS: The frequency distribution of the proguanil metabolic ratio ranged from 0.01 to 39.64 with a median of 1.38 in the 126 Nigerians. On the basis of the antimode value of 10 for the proguanil/cycloguanil ratio, the prevalence of poor metabolisers in this Nigerian population was estimated to be 4.8% (6 of 126), which is very similar to that of S-mephenytoin (4.3%) found in a previous study in Nigerians. The data also demonstrated enormous inter-individual differences in the urinary proguanil/cycloguanil ratios with poor metabolisers excreting, on average, only about 8% of the quantity of cycloguanil excreted by extensive metabolisers. CONCLUSION: The incidence of phenotypically poor metabolisers of proguanil in this Nigerian population is similar to those reported for Caucasian and other African populations but is much lower than those reported for Orientals. The study further supports previous studies that proguanil can be used as an alternative probe to phenotype for CYP2C19 activity.     

Antipyrine disposition in obesity: evidence for negligible effect of obesity on hepatic oxidative metabolism

Following an overnight fast and 2 days of abstention from caffeine, a single 1.0-g oral dose of antipyrine was administered to 20 obese but otherwise healthy subjects (group A) and 11 healthy volunteers (group B). Weight, Body Mass Index (BMI) and % of Ideal Body Weight (IBW) were significantly greater in the obese than in the lean group. (Mean 110.4 vs 62.7 kg; 38.5 vs 22.3 kg · m^–2 and 181vs 106 % respectively). In a subgroup of 6 obese subjects (group C) antipyrine was given again 11.3 months later after a 29.8 kg mean weight loss.Antipyrine apparent volume of distribution (V) and elimination half-life (t _1/2) were significantly greater in the obese than in the lean group (V 49.9 vs 34.3 l respectively; t _1/2 15.5 vs 12.0 h respectively), but its clearance rate (CL_o) values were similar. V corrected for total body weight was significantly reduced in group A than in group B (0.45 vs 0.55 l · kg^–1 respectively). Stratified comparison of antipyrine pharmacokinetics between obese and lean subjects according to age, gender and smoking habits did not alter the overall results. In group C, weight reduction was associated with a significant decrease in antipyrine V (from 51.8 to 47.5 l) and t _1/2 (from 15.1 to 12.7 h), and a non-significant increase in antipyrine CL_o.We conclude that in severely obese subjects, antipyrine total V is mildly increased but V corrected for total body weight is significantly decreased. In addition, obesity is associated with a slight prolongation of antipyrine t _1/2 whereas its CL_o is unaltered. These findings may indicate that obesity, even in its extreme form, has a negligible effect on the oxidative metabolic capacity of the liver.     

肾移植受者CYP3A5基因多态性对他可莫司代谢的影响

目的研究CYP3A基因多态性对肾移植受者他可莫司代谢的影响。方法50例肾移植受者采用FK506＋霉酚酸酯＋强的松三联免疫抑制方案,FK506起始剂量0．15mg／（kg·d）,1w后根据目标血药浓度调整。CYP3A5基因多态性检测采用聚合酶链反应-限制性片段长度多态性（PCR—RFLP）方法,50例肾移植受者分为＊1／＊1型（12例）、＊1／＊3型（16例）、＊3／＊3型（22例）共3组。比较6个月内FK506的血药浓度／剂量比。结果 肾移植术后7天、1月、3月、6月＊3／＊3型患者FK506的血药浓度／剂量比显著高于＊1／＊1型和＊1／＊3型（P〈0．05）。结论由于CYP3A5基因多态性影响,＊1／＊1型组的患者早期难以达到有效FK506目标血药浓度,应该提高该组患者的起始用药剂量,根据CYP3A5基因多态性作为FK506个体化用药的依据,可以减少早期急性排斥反应,提高肾移植的临床效果。     

CYP2C19基因多态性对药物代谢的影响及其个体化用药

CYP2C19是一种重要的药物代谢酶,参与多种药物的体内代谢。该酶的活性在不同个体和种族之间存在着显著的差异。本文综述了CYP2C19酶的基因多态性对药物代谢的影响,以期为指导临床合理用药打下坚实的理论基础,确保临床用药的安全性和有效性,真正的实现个体化用药。     

Effect of oxidative polymorphism (debrisoquine/sparteine type) on hepatic first-pass metabolism of bufuralol

Summary Bufuralol is a beta-adrenoceptor blocking drug whose oxidative metabolism is under the same genetic control as debrisoquine and sparteine. The pharmacokinetics of bufuralol were studied in 10 healthy subjects (7 extensive and 3 poor metabolizers of debrisoquine) after oral and intravenous administration. In extensive metabolizers the systemic availability of bufuralol was 43%. Poor metabolizers were characterized by a considerable increase in systemic availability due to a corresponding decrease in hepatic first-pass metabolism. After oral administration of bufuralol non-linear kinetics may occur.