Abstract：
AIMS:The role of CYP pharmacogenetics in the bioactivation of cyclophosphamide is still controversial. Recent clinical studies have suggested a role for either CYP2C19 or CYP2B6. The aim of this study was to clarify the role of these pharmacogenes. METHODS:We used a combined in vitro-in vivo approach to determine the role of these pharmacogenes in the bioactivation of the prodrug to 4-hydroxy cyclophosphamide (4-OHCP). Cyclophosphamide metabolism was determined in a human liver biobank (n= 14) and in patients receiving the drug for treatment of lupus nephritis (n= 16) RESULTS:In livers of known CYP2C19 and CYP2B6 genotype and protein expression we observed that there was a combined role for both CYP2C19 and CYP2B6 in the bioactivation of cyclophosphamide in vitro. The presence of at least one loss of function (LoF) allele at either CYP2C19 or CYP2B6 resulted in a significant decrease in both V(max) (P= 0.028) and CL(int) (P= 0.0017) compared with livers with no LoF alleles. This dual genotype relationship was also observed in a preliminary clinical study, with patients who had ≥1 LoF allele at either CYP2C19 or CYP2B6 also displaying significantly (P= 0.0316) lower bioactivation of cyclophosphamide. The mean 4-OHCP : CP bioactivation ratio was 0.0014 (95% CI 0.0007, 0.002) compared with 0.0071 (95% CI 0.0001, 0.014) in patients with no LoF alleles at either of these genes. CONCLUSIONS:The presence of ≥1 LoF allele(s) at either CYP2B6 or CYP2C19 appeared to result in decreased bioactivation of cyclophosphamide both in vitro and in patients. Further clinical studies to confirm this relationship are warranted.
journal_name
Br J Clin Pharmacoljournal_title
British journal of clinical pharmacologyauthors
Helsby NA,Hui CY,Goldthorpe MA,Coller JK,Soh MC,Gow PJ,De Zoysa JZ,Tingle MDdoi
10.1111/j.1365-2125.2010.03789.xsubject
Has Abstractpub_date
2010-12-01 00:00:00pages
844-53issue
6eissn
0306-5251issn
1365-2125journal_volume
70pub_type
杂志文章abstract：AIMS:The aims of the present study were to describe the consumption trends of three groups of analgesics (non-opioids, and mild and strong opioids) between 2006 and 2015 in France, and compare this pattern of use with six European countries in 2015. METHODS:Annual drugs sales were extracted from the French national au...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/bcp.13564
更新日期：2018-06-01 00:00:00
abstract：:1. In order to assess attitudes of patients to participation in therapeutic trials 197 patients underwent structured interviews conducted by a single observer. Of these patients 66 were previous or current participants in clinical trials (group A), 12 had declined participation in a trial (group B), and 119 had never ...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：
更新日期：1993-02-01 00:00:00
abstract：AIMS:Helicobacter pylori (H. pylori) eradication rate varies according to the treatment regimen used and other factors, e.g. antimicrobial resistance and patient compliance. The aim of the present study was to evaluate the influence of patient counselling and follow-up on H. pylori eradication rates and to document the...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1046/j.0306-5251.2001.01531.x
更新日期：2002-02-01 00:00:00
abstract：AIMS:Angiotensin II is a putative mediator in bronchial asthma. There have been very few studies investigating the involvement of angiotensin II receptors in bronchial hyper-responsiveness in asthmatic patients. We examined the effect of candesartan cilexetil, a specific angiotensin II type 1 (AT1) receptor antagonist,...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1046/j.1365-2125.2002.t01-4-01689.x
更新日期：2002-12-01 00:00:00
abstract：:The ability to recall details of current and prior drug therapy was evaluated in two studies employing a total of 94 patients with inflammatory polyarthritis. Ten per cent of patients were unable to completely recall the names of their current anti-inflammatory drugs and eighty-three per cent of patients to completely...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1984.tb02417.x
更新日期：1984-06-01 00:00:00
abstract：AIMS:Hypertension is a common comorbidity of patients with COVID-19, SARS or HIV infection. Such patients are often concomitantly treated with antiviral and antihypertensive agents, including ritonavir and nifedipine. Since ritonavir is a strong inhibitor of CYP3A and nifedipine is mainly metabolized via CYP3A, the com...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/bcp.14684
更新日期：2020-12-02 00:00:00
abstract：AIMS:Drug disposition in children may vary from adults due to age-related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however, they should be used only when the PK is dose linear. We aimed to assess dose linearity of a [14 C]midazolam microdose, b...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,多中心研究
doi：10.1111/bcp.14047
更新日期：2019-10-01 00:00:00
abstract：AIMS:The primary objective of this study was to characterize the pharmacokinetics and pharmacodynamics of single daily doses of donepezil (5 and 10 mg) each evening for 28 consecutive days. A secondary objective was to measure the plasma protein binding of donepezil at steady state. METHODS:This was a double-blind, ra...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1046/j.1365-2125.1998.0460s1013.x
更新日期：1998-11-01 00:00:00
abstract：AIMS:Mexiletine has been reported to be hydroxylated by cytochrome P450 2D6 (CYP2D6) in humans. However, the involvement of CYP1A2 in the metabolism of mexiletine has been proposed based on the interaction with theophylline which is mainly metabolized by CYP1A2. The aim of this study was to clarify the role of human CY...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1046/j.1365-2125.1998.00048.x
更新日期：1998-07-01 00:00:00
abstract：AIMS:The aim of the present study was to assess the effect of policy interventions - i.e. reimbursement decisions, guidelines and regional recommendations - on the prescribing of oral anticoagulant treatment in patients with atrial fibrillation (AF). METHODS:Interrupted time series analyses were carried out using mont...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/bcp.13150
更新日期：2017-03-01 00:00:00
abstract：:1. The attitudes of general practitioners and hospital physicians to the management of hypertension in the elderly, were examined by responses to a postal questionnaire distributed within the Northern Region, concerning the management of a healthy 75 year old male non-smoker with sustained diastolic or isolated systol...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1995.tb04481.x
更新日期：1995-05-01 00:00:00
abstract：:The effect of fatty degeneration of liver parenchyma on drug metabolism was investigated in 21 obese non-insulin-dependent diabetic subjects by measuring plasma antipyrine kinetics, hepatic cytochrome P-450, liver size and the extent of fatty infiltration. The hepatic drug metabolising capacity, as measured by total a...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1984.tb02561.x
更新日期：1984-12-01 00:00:00
abstract：:The effects of separate 7 day pretreatments with sulphinpyrazone (800 mg daily) and cimetidine (1 g daily) on the disposition of (+/-)-verapamil have been examined in eight healthy volunteers (four male, four female). Each subject received single oral (80 mg) and intravenous (0.15 mg/kg) doses of verapamil on differen...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1985.tb02658.x
更新日期：1985-03-01 00:00:00
abstract：:1. Hydrochlorothiazide (HCT, 50-75 mg) was administered orally to seven patients with cardiac failure. 2. Plasma levels and urinary concentration of HCT were determined by GLC. 3. The gastrointestinal uptake of the diuretic in three patients was reduced to approximately half that seen in healthy controls. 4. Plasma ha...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1979.tb04646.x
更新日期：1979-06-01 00:00:00
abstract：:1 This study was designed to compare in a double-blind randomized crossover trial, atenolol, labetalol, metoprolol and pindolol. Considerable differences in dose (atenolol 138 +/- 13 mg daily; labetalol 308 +/- 34 mg daily; metoprolol 234 +/- 22 mg daily; and pindolol 24 +/-2 mg daily were required to produce similar ...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1979.tb04774.x
更新日期：1979-04-01 00:00:00
abstract：:1 The effects of the thromboxane synthetase inhibitor dazoxiben (UK 37248) on haemodynamics, blood gases, thromboxane and prostacyclin release and on arrhythmias were examined in anaesthetised greyhounds subject to acute coronary artery occlusion and reperfusion. 2 Ten minutes after the administration of UK 37248 2 mg...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1983.tb02115.x
更新日期：1983-01-01 00:00:00
abstract：:1 The haemodynamic effects of labetalol 50 mg intravenously were studied in 13 hypertensive patients at rest in the supine and upright positions and during exercise using percutaneous right heart and brachial artery catheterization. 2 Labetalol induced immediate significant reductions in systolic and diastolic blood p...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：
更新日期：1976-08-01 00:00:00
abstract：AIM:Drug-drug interactions between antimalarial and antiretroviral drugs may influence antimalarial treatment outcomes. The aim of this study was to investigate the potential drug-drug interactions between the antimalarial drugs, lumefantrine, artemether and their respective metabolites desbutyl-lumefantrine and dihydr...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1111/bcp.12529
更新日期：2015-04-01 00:00:00
abstract：:A method is described for the simultaneous determination of the carboxylic acid and N-acetyl-derivatives of primaquine, in plasma and urine. After oral administration of 45 mg primaquine, to five healthy volunteers, absorption was rapid, with peak primaquine levels of 153.3 +/- 23.5 ng/ml at 3 +/- 1 h, followed by an ...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1984.tb02369.x
更新日期：1984-04-01 00:00:00
abstract：AIMS:We performed a prospective cohort study to gain more insight into risk factors for neuropsychiatric effects of mefloquine among tourists travelling to tropical areas. METHODS:We enrolled all patients who consulted the Travel Clinic of the Havenziekenhuis & Institute for Tropical Diseases Rotterdam for mefloquine ...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1046/j.1365-2125.2003.02035.x
更新日期：2004-04-01 00:00:00
abstract：:1. The metabolic oxidation of debrisoquine (DB) was studied in 89 non-related Cuna Amerindian subjects. 2. Means and standard deviations for urinary recoveries of the intact drug and its 4-hydroxy metabolite (4-HD) were: %DB: 6.8 +/- 4.5; %4-HD: 16.0 +/- 9.1; %sum: 22.8 +/- 12.0. The log10 metabolic ratios for DB (LMR...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1990.tb03776.x
更新日期：1990-08-01 00:00:00
abstract：:The steady-state pharmacokinetic interaction between nefazodone and cimetidine was evaluated in a three-period crossover study consisting of three treatments of 1 week duration with a 1 week washout between treatments. The 18 healthy, male study subjects received: nefazodone hydrochloride 200 mg twice daily (every 12 ...
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.1365-2125.1995.tb05771.x
更新日期：1995-08-01 00:00:00
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
更新日期：1991-06-01 00:00:00
abstract：AIMS:This study compares physicians' recall of the claims of benefits on cardiovascular disease and diabetes made by pharmaceutical sales representatives for drugs approved on the basis of a surrogate outcome, i.e., an off-label claim, compared with those approved on the basis of a serious morbidity or mortality (clini...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/bcp.13360
更新日期：2017-11-01 00:00:00
abstract：AIMS:To investigate the effect of multiple dosing with montelukast, a selective leukotriene-receptor antagonist, on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans. METHODS:A two-period, randomized crossover study was conducted in 10 healthy subjects. After administration of oral doses of placebo ...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1111/j.1365-2125.2006.02764.x
更新日期：2007-03-01 00:00:00
abstract：:1. Mizolastine, a new benzimidazole derivative with potent selective, non-sedative H1-histamine antagonist activity was compared with terfenadine, cetirizine and loratadine using the histamine-induced wheal and flare model in healthy volunteers. 2. Study design was a five way double-blind crossover design using a sing...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：
更新日期：1995-11-01 00:00:00
abstract：:A potential kinetic interaction between cimetidine and flecainide has been studied in eight healthy males receiving flecainide (200 mg) orally on three occasions: before any treatment and on day 2 and day 7 of 8 days' cimetidine maintenance treatment at 1 g daily. Six days pretreatment with cimetidine induced the foll...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：
更新日期：1986-07-01 00:00:00
abstract：WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT:• Clinical cases reported that fatal acute liver failure occurred when paracetamol (acetaminophen) was co-administrated with some tyrosine kinase inhibitors (TKIs). The direct inhibition of UDP-glucuronosyltransferase activities has been identified as a mechanism of potentiation...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.2011.03911.x
更新日期：2011-06-01 00:00:00
abstract：:This is the second of two papers which review issues concerning complementary medicines. The first reviewed the extent of use of complementary medicines, and issues related to the regulation and pharmaceutical quality of these products; the second considers evidence for the efficacy of several well-known complementary...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,评审
doi：10.1046/j.1365-2125.2003.01811.x
更新日期：2003-04-01 00:00:00
abstract：AIMS:It has been shown that the cellular uptake and cytotoxicity of anthracyclines decrease with increasing cell density in vitro, an event termed 'the inocculum effect'. It is not known whether such an effect occurs in vivo. In this study the relationships between white blood cell (WBC) count, plasma and cellular conc...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.2010.03894.x
更新日期：2011-04-01 00:00:00
