Pharmacokinetics of lamotrigine and its metabolite N-2-glucuronide: Influence of polymorphism of UDP-glucuronosyltransferases and drug transporters.

Abstract:

AIMS:This study aimed to develop a population pharmacokinetic model for quantitative evaluation of the influence of genetic variants in metabolic enzymes and transporters on lamotrigine pharmacokinetics while taking into account the influence of various clinical, biochemical and demographic factors. METHODS:We included 100 patients with epilepsy on stable dosing with lamotrigine as mono or adjunctive therapy. Lamotrigine and lamotrigine N-2-glucuronide concentrations were determined in up to two plasma samples per patient. Patients were genotyped for UGT1A4, UGT2B7, ABCB1 and SLC22A1. Population pharmacokinetic analysis was performed by non-linear mixed effects modelling. Prior knowledge from previous pharmacokinetic studies was incorporated to stabilize the modelling process. A parent-metabolite model was developed to get a more detailed view on the covariate effects on lamotrigine metabolism. RESULTS:With a base model absorption rate (interindividual variability) was estimated at 1.96 h(-1) (72.8%), oral clearance at 2.32 l h(-1) (41.4%) and distribution volume at 77.6 l (30.2%). Lamotrigine clearance was associated with genetic factors, patient's weight, renal function, smoking and co-treatment with enzyme inducing or inhibiting drugs. In patients with UGT2B7-161TT genotype clearance was lower compared with GT and GG genotypes. Clearance was particularly high in patients with UGT2B7 372 GG genotype (compared with AA genotype it was 117%; 95% CI 44.8, 247% higher). CONCLUSIONS:Variability in lamotrigine pharmacokinetics is large and quantification of its sources may lead to more precise individual treatment. Genotyping for UGT2B7 may be useful in various clinical settings.

journal_name

Br J Clin Pharmacol

authors

Milosheska D,Lorber B,Vovk T,Kastelic M,Dolžan V,Grabnar I

doi

10.1111/bcp.12984

subject

Has Abstract

pub_date

2016-08-01 00:00:00

pages

399-411

issue

2

eissn

0306-5251

issn

1365-2125

journal_volume

82

pub_type

临床试验,杂志文章
  • Oxidation of reduced haloperidol to haloperidol: involvement of human P450IID6 (sparteine/debrisoquine monooxygenase).

    abstract::1. The conversion of haloperidol (HAL) to reduced haloperidol (RHAL) and then back to HAL has been established in vivo and observed in psychiatric patients. The reduction of HAL to RHAL is known to be catalysed by a ketone reductase, while the nature of oxidation back to HAL is the subject of the present study. 2. We ...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.1991.tb05588.x

    authors: Tyndale RF,Kalow W,Inaba T

    更新日期:1991-06-01 00:00:00

  • The effects of beta-adrenoceptor blockade on renin, angiotensin, aldosterone and catecholamines at rest and during exercise.

    abstract::1 beta-adrenoceptor blockade with metoprolol provoked, both at rest and during exercise, a decrease of 'active' renin and angiotensin II together with an increase of 'inactive' renin and unchanged 'total' renin. The significant exercise-provoked increases in angiotensin II, plasma renin activity and 'active', 'inactiv...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1111/j.1365-2125.1979.tb00918.x

    authors: Lijnen PJ,Amery AK,Fagard RH,Reybrouck TM,Moerman EJ,De Schaepdryver AF

    更新日期:1979-02-01 00:00:00

  • Developmental pharmacokinetics of propylene glycol in preterm and term neonates.

    abstract:AIM:Propylene glycol (PG) is often applied as an excipient in drug formulations. As these formulations may also be used in neonates, the aim of this study was to characterize the pharmacokinetics of propylene glycol, co-administered intravenously with paracetamol (800 mg PG/1000 mg paracetamol) or phenobarbital (700 mg...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.2012.04312.x

    authors: De Cock RF,Knibbe CA,Kulo A,de Hoon J,Verbesselt R,Danhof M,Allegaert K

    更新日期:2013-01-01 00:00:00

  • The negative inotropic and chronotropic effects of intravenous R 56865 during percutaneous transluminal coronary angioplasty.

    abstract::The present study was designed to evaluate the potential anti-ischaemic activity of R 56865 in patients with coronary artery disease, scheduled to undergo percutaneous transluminal coronary angioplasty (PTCA). At baseline a complete haemodynamic profile, including cardiac output and coronary sinus blood flow (CSBF) wa...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章

    doi:10.1111/j.1365-2125.1995.tb04491.x

    authors: Pijl AJ,Van Wezel HB,Koolen JJ,Piek JJ,Koch K,Swaan A,David GK,Visser CA,Van Zwieten PA

    更新日期:1995-05-01 00:00:00

  • Chemical design of cilazapril.

    abstract::1. The three dimensional requirements for inhibition of ACE (angiotensin converting enzyme) were investigated in order to facilitate design of a more potent and selective antihypertensive agent. 2. All compounds designed possessed a bicyclic unit incorporating carboxylate and amidic carbonyl groups together with a thi...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.1989.tb03474.x

    authors: Attwood MR

    更新日期:1989-01-01 00:00:00

  • Blood pressure response to labetalol in twice and three times daily administration during a 24-hour period.

    abstract::1 The anti-hypertensive effect of labetalol given twice or three times daily was evaluated in ambulant subjects with essential hypertension by recording blood pressure directly for 24 h before and after 15 d of labetalol administration (daily dose 600-1800 mg). 2 Labetalol reduced 24 h systolic and diastolic blood pre...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.1982.tb01886.x

    authors: Mancia G,Pomidossi G,Parati G,Bertinieri G,Grassi G,Navone F,Ferrari A,Gregorini L,Zanchetti A

    更新日期:1982-06-01 00:00:00

  • Betaxolol and glucose-insulin relationships: studies in normal subjects taking glibenclamide or metformin.

    abstract::1. The potential interaction between selective beta 1-adrenoceptor blockers and sulphonylureas or biguanides was studied by comparing the beta 1-adrenoceptor antagonist betaxolol with placebo in 12 normal subjects taking glibenclamide or metformin in a single-blind crossover group study. 2. After a 4 day run-in period...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1111/j.1365-2125.1990.tb03838.x

    authors: Sinclair AJ,Davies IB,Warrington SJ

    更新日期:1990-11-01 00:00:00

  • Initial therapy, persistence and regimen change in a cohort of newly treated type 2 diabetes patients.

    abstract:AIMS:The aim was to describe the utilization of antidiabetic agents, in terms of persistence and regimen change, in the management of a cohort of newly treated type 2 diabetes patients and to investigate associated socio-demographic and treatment factors. METHODS:A population-based retrospective cohort study was condu...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/bcp.12573

    authors: Grimes RT,Bennett K,Tilson L,Usher C,Smith SM,Henman MC

    更新日期:2015-06-01 00:00:00

  • Concentration-response relationships for salicylate-induced ototoxicity in normal volunteers.

    abstract::1. Ototoxicity is a common and troublesome side-effect of high-dose aspirin treatment but there has been little previous study of the relationships between the degree of ototoxicity and the plasma concentrations of salicylate. 2. In order to investigate the relationships between aspirin dose, total and unbound plasma ...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1111/j.1365-2125.1989.tb03562.x

    authors: Day RO,Graham GG,Bieri D,Brown M,Cairns D,Harris G,Hounsell J,Platt-Hepworth S,Reeve R,Sambrook PN

    更新日期:1989-12-01 00:00:00

  • Plasma melatonin during desmethylimipramine treatment: evidence for changes in noradrenergic transmission.

    abstract::Plasma melatonin was used to determine overall beta-adrenergic transmission through pineal neuro-effector junctions during desmethylimipramine (DMI) treatment in 10 normal subjects. Changes in plasma melatonin indicated that an initial increase in noradrenaline (NA) transmission produced by DMI was counteracted by ada...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.1985.tb02717.x

    authors: Cowen PJ,Green AR,Grahame-Smith DG,Braddock LE

    更新日期:1985-06-01 00:00:00

  • Lack of inhibitory effect of cimetidine on caffeine metabolism in children using the caffeine breath test.

    abstract:AIMS:To study the potential drug interaction between cimetidine and caffeine in a group of children who received cimetidine for gastritis. METHODS:The caffeine breath test was carried out prior to the administration of cimetidine and after 2-3 weeks therapy. The children (n = 1) received 300-800 mg cimetidine daily (1...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章

    doi:10.1046/j.1365-2125.1997.00589.x

    authors: Parker AC,Pritchard P,Preston T,Dalzell AM,Choonara I

    更新日期:1997-05-01 00:00:00

  • Excretion of chloroquine, dapsone and pyrimethamine in human milk.

    abstract::The concentration of chloroquine (CQ), dapsone (DDS) and pyrimethamine (PYR) in plasma and milk were measured following the coadministration of a single dose of chloroquine and Maloprim to lactating women. The milk to plasma area under the concentration-time curve (AUC) ratio ranged from 1.96 to 4.26 for CQ, 0.22 to 0...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.1986.tb02967.x

    authors: Edstein MD,Veenendaal JR,Newman K,Hyslop R

    更新日期:1986-12-01 00:00:00

  • Effects of MHRA drug safety advice on time trends in prescribing volume and indices of clinical toxicity for quinine.

    abstract:AIMS:To ascertain the effects of the Medicines and Healthcare products Regulatory Agency's (MHRA) safety update in June 2010 on the volume of prescribing of quinine and on indices of quinine toxicity. METHODS:We analysed quarterly primary care total and quinine prescribing data for England and quinine prescribing volu...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/bcp.12130

    authors: Acheampong P,Cooper G,Khazaeli B,Lupton DJ,White S,May MT,Thomas SH

    更新日期:2013-12-01 00:00:00

  • The effects of alpha- and beta-adrenergic receptor blockers on the pressure responses to isometric exercise in hypertensive patients.

    abstract::1. The cardiovascular responses to handgrip exercise have been studied in ten patients with uncomplicated essential hypertension in a randomized crossover study of propranolol and prazosin. 2. Isometric handgrip exercise was performed with a calibrated strain gauge dynamometer at 30% of maximum voluntary contraction f...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1111/j.1365-2125.1979.tb04720.x

    authors: Reuben SR,Gale EV,Blake P

    更新日期:1979-10-01 00:00:00

  • Commentary on the EMA Reflection Paper on the use of extrapolation in the development of medicines for paediatrics.

    abstract::Adopted guidelines reflect a harmonised European approach to a specific scientific issue and should reflect the most recent scientific knowledge. However, whilst EU regulations are mandatory for all member states and EU directives must be followed by national laws in line with the directive, EMA guidelines do not have...

    journal_title:British journal of clinical pharmacology

    pub_type:

    doi:10.1111/bcp.13883

    authors: Ollivier C,Thomson A,Manolis E,Blake K,Karlsson KE,Knibbe CAJ,Pons G,Hemmings R

    更新日期:2019-04-01 00:00:00

  • Does it matter where we measure blood pressure?

    abstract::Although blood pressure measured at the brachial artery plays a central role in our understanding and management of cardiovascular risk, in recent years great emphasis has been placed on the importance of central blood pressure. It seems straightforward that knowledge of the blood pressure directly affecting the major...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章,评审

    doi:10.1111/j.1365-2125.2012.04203.x

    authors: Tomlinson LA,Wilkinson IB

    更新日期:2012-08-01 00:00:00

  • Intrinsic heart rate on exercise and the measurement of beta-adrenoceptor blockade.

    abstract::Methods of expressing the effects of beta-adrenoceptor blocking drugs on exercise heart rate have been evaluated using a standardised exercise test. In six normal subjects given atropine (0.04 mg/kg) on two separate occasions, the mean +/- s.e. mean exercise heart rate rose by 10.3 +/- 1.8 beats/min and by 11.0 +/- 1....

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.1976.tb00348.x

    authors: Carruthers SG,Shanks RG,McDevitt DG

    更新日期:1976-12-01 00:00:00

  • Hospitalization as an opportunity to correct errors in anticoagulant treatment in patients with atrial fibrillation.

    abstract:AIMS:To assess whether hospitalization may assist in correcting errors in anticoagulant therapy among patients with atrial fibrillation (AF). METHODS:Our cohort included patients admitted to our institution with a history of AF between 2016 and 2018. We categorized patient's treatment upon admission and discharge as l...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/bcp.14116

    authors: Angel Y,Zeltser D,Berliner S,Ingbir M,Shapira I,Shenhar-Tsarfaty S,Rogowski O

    更新日期:2019-12-01 00:00:00

  • No significant effect of ABCB1 haplotypes on the pharmacokinetics of fluvastatin, pravastatin, lovastatin, and rosuvastatin.

    abstract:AIMS:This study aimed to investigate possible effects of ABCB1 genotype on fluvastatin, pravastatin, lovastatin, and rosuvastatin pharmacokinetics. METHODS:In a fixed-order crossover study, 10 healthy volunteers with the ABCB1 c.1236C/C-c.2677G/G-c.3435C/C (CGC/CGC) genotype and 10 with the c.1236T/T-c.2677T/T-c.3435T...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.2009.03440.x

    authors: Keskitalo JE,Kurkinen KJ,Neuvonen M,Backman JT,Neuvonen PJ,Niemi M

    更新日期:2009-08-01 00:00:00

  • Anti-factor Xa activity of enoxaparin administered at prophylactic dosage to patients over 75 years old.

    abstract:AIMS:Major bleeding complications with low-molecular-weight heparin (LMWH) treatment have been reported both in clinical studies and during postmarketing surveillance. Monitoring of antifactor Xa (anti-Xa) activities is therefore recommended in special populations often predisposed to renal impairment. The PROPHRE.75 s...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.2007.02920.x

    authors: Berges A,Laporte S,Epinat M,Zufferey P,Alamartine E,Tranchand B,Decousus H,Mismetti P,PROPHRE.75 Study Group.

    更新日期:2007-10-01 00:00:00

  • The pharmacokinetics, antihistamine and concentration-effect relationship of ebastine in healthy subjects.

    abstract::1. The kinetics and effects of ebastine 10 and 50 mg were studied after oral dosing in healthy subjects. 2. The parent drug was extensively metabolised during the first pass to its carboxylic acid derivative, carebastine. 3. The pharmacokinetics of carebastine were linear over the dose range studied and the terminal e...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1111/j.1365-2125.1988.tb05288.x

    authors: Vincent J,Liminana R,Meredith PA,Reid JL

    更新日期:1988-11-01 00:00:00

  • Quality and safety of herbal medical products: regulation and the need for quality assurance along the value chains.

    abstract::Herbal medicines and products derived from them are a diverse group of products for which different (and often limited) levels of evidence are available. As importantly, such products generally vary in their composition and are at the end of an often poorly understood value chain, which often links producers in biodiv...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章,评审

    doi:10.1111/bcp.12586

    authors: Heinrich M

    更新日期:2015-07-01 00:00:00

  • Pharmacokinetics and bioavailability of midazolam in man.

    abstract::The pharmacokinetic behaviour and the bioavailability of midazolam were investigated in six volunteers after intravenous (0.15 mg/kg) and oral administration (10, 20 and 40 mg). Following rapid intravenous injection of midazolam, the plasma concentration of the substance decreased to approximately 10% within 2 h owing...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.1983.tb02270.x

    authors: Heizmann P,Eckert M,Ziegler WH

    更新日期:1983-01-01 00:00:00

  • Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain.

    abstract:AIMS:It is estimated that two-thirds of cancer patients will at some point during their illness experience breakthrough pain. In this study, the pharmacokinetics of a novel sublingual dosage form of fentanyl developed for breakthrough pain was evaluated. METHODS:Eleven Caucasian patients (seven male and 4 female, aged...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1111/j.1365-2125.2004.02264.x

    authors: Lennernäs B,Hedner T,Holmberg M,Bredenberg S,Nyström C,Lennernäs H

    更新日期:2005-02-01 00:00:00

  • Romiplostim dose-response in patients with myelodysplastic syndromes.

    abstract:AIM:To characterize the romiplostim dose-response in subjects with low or intermediate-1 risk myelodysplastic syndromes (MDS) receiving subcutaneous romiplostim. METHODS:Data from 44 MDS subjects receiving subcutaneous romiplostim (dose range 300-1500 μg week(-1) ) were used to develop a pharmacodynamic model consisti...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/bcp.12041

    authors: Perez Ruixo JJ,Doshi S,Wang YM,Mould DR

    更新日期:2013-06-01 00:00:00

  • Moxifloxacin-induced QTc interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study.

    abstract:AIM:We investigated whether moxifloxacin-induced QTc prolongations in Japanese and Caucasian healthy male volunteers were significantly different. METHODS:A two period, randomized, crossover, ICH-E14-compliant thorough QT (TQT) study compared placebo-corrected changes in QTc interval from baseline (ΔΔQTc F) and concen...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章,随机对照试验

    doi:10.1111/bcp.12684

    authors: Morganroth J,Wang Y,Thorn M,Kumagai Y,Harris S,Stockbridge N,Kleiman R,Shah R

    更新日期:2015-09-01 00:00:00

  • Mexiletine disposition: individual variation in response to urine acidification and alkalinisation.

    abstract::The disposition of mexiletine has been studied in five subjects on two occasions with urine pH controlled at 5.0 and at 8.0. With acid urine total plasma clearance was similar in all subjects (462 to 497 ml min-1) and the plasma half-life ranged from 3.8 to 9.2 h (mean 6.7 h). With alkaline urine the total plasma clea...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.1983.tb02162.x

    authors: Mitchell BG,Clements JA,Pottage A,Prescott LF

    更新日期:1983-09-01 00:00:00

  • Quality of requests for serum digoxin concentrations: experience from an Australian regional health service.

    abstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT:* Therapeutic drug monitoring of serum digoxin concentrations (SDC) is considered useful in enhancing the therapeutic benefits of digoxin and minimizing the incidence of adverse drug reactions. * The quality of requests for SDC has been reported to be generally unsatisfactory. H...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.2006.02802.x

    authors: Ellington C,Grgurinovich N,Miners JO,Mangoni AA

    更新日期:2007-05-01 00:00:00

  • The pharmacokinetics of the enantiomers of flurbiprofen in patients with rheumatoid arthritis.

    abstract::Plasma and synovial fluid concentrations of the enantiomers of flurbiprofen were measured in 15 rheumatoid patients receiving 100 mg racemic flurbiprofen twice daily. Pharmacokinetic parameters showed considerable variability within the group of patients, although differences in S(+)/R(-) plasma concentration ratios w...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.1991.tb03865.x

    authors: Young MA,Aarons L,Toon S

    更新日期:1991-01-01 00:00:00

  • A gastroscopic and pharmacological study of the disintegration time and absorption of pivampicillin capsules and tablets.

    abstract::1 An in vitro investigation showed that pivampicillin tablets disintegrated more rapidly than pivampicillin capsules. This result was demonstrated and confirmed by gastroscopy in a cross-over study in healthy volunteers. 2 There were no differences in serum levels of ampicillin obtained with the two preparations, but ...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1111/j.1365-2125.1979.tb01008.x

    authors: Hey H,Matzen P,Andersen JT,Didriksen E,Nielsen B

    更新日期:1979-09-01 00:00:00