Abstract:
:Clinical investigations using isoform-selective probes to phenotype cytochrome P450 activity and interaction studies using isoform-selective inhibitors to determine P450 involvement in drug metabolism assume minimal interday variability in P450 activity. CYP3A4 is the most abundant human P450 isoform and metabolizes approximately half of all therapeutic agents. This investigation evaluated interday variability in hepatic CYP3A4 activity in males, using the clearances of midazolam and alfentanil as metabolic probes. Midazolam (1 mg) followed 1 hour later by alfentanil (20 micrograms/kg) were administered by intravenous bolus to 9 nonsmoking male volunteers (ages 30 +/- 8 years). Drug administration was repeated 12 and 20 days later. Venous plasma midazolam and alfentanil concentrations were determined by gas chromatography/mass spectrometery. Drug clearances were determined by noncompartmental and multiexponential analysis. There were no significant interday differences in plasma drug concentrations or clearances (3.9 +/- 1.4, 3.9 +/- 1.7, and 4.2 +/- 1.7 ml/kg/min for alfentanil, respectively, and 6.6 +/- 2.0, 7.9 +/- 2.4, and 7.9 +/- 2.5 ml/kg/min for midazolam, respectively, on days 1, 13, and 21 [mean +/- SD]). Interday variability in clearance was 13% +/- 6% and 19% +/- 12% for alfentanil and midazolam, respectively. Interday variability in the clearance of these probes, and presumably hepatic CYP3A4 activity, was small compared with interindividual variability. Consideration of interday variability in the hepatic metabolism of CYP3A4 substrates does not appear significant in the design of clinical trials.
journal_name
J Clin Pharmacoljournal_title
Journal of clinical pharmacologyauthors
Kharasch ED,Jubert C,Senn T,Bowdle TA,Thummel KEdoi
10.1177/00912709922008290subject
Has Abstractpub_date
1999-07-01 00:00:00pages
664-9issue
7eissn
0091-2700issn
1552-4604journal_volume
39pub_type
临床试验,杂志文章abstract::Forty-two healthy Caucasian subjects were randomized in a double-blind, parallel three-group study (14 subjects per group) to investigate potential electrocardiographic and pharmacokinetic interactions between the antimalarials artemether-lumefantrine (six-dose regimen of Riamet over 3 days) and quinine (2-h intraveno...
journal_title:Journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1177/009127002401382632
更新日期:2002-10-01 00:00:00
abstract::Fosamprenavir (FPV) is the phosphate ester prodrug of the HIV-1 protease inhibitor amprenavir (APV). A pediatric population pharmacokinetic model for APV was developed and simulation was used to identify dosing regimens for pediatric patients receiving FPV in combination with ritonavir (RTV) which resulted in concentr...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/jcph.205
更新日期:2014-02-01 00:00:00
abstract::Two phase I open-label studies were conducted to investigate the pharmacokinetics (PK), safety, and tolerability of single oral doses of selumetinib in subjects with end-stage renal disease (ESRD) undergoing hemodialysis and subjects with varying degrees of hepatic impairment; both studies included a matched control g...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/jcph.848
更新日期:2017-05-01 00:00:00
abstract::The primary objective of the current investigation was to establish the pharmacokinetic characteristics of oxymetazoline and tetracaine's primary metabolite, para-butylaminobenzoic acid (PBBA), after the intranasal administration of oxymetazoline/tetracaine. Thirty-six subjects contributing a total of 1791 plasma conc...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/jcph.799
更新日期:2017-02-01 00:00:00
abstract::Possible effects of multiple-dose administration of atorvastatin on the pharmacokinetics of single-dose antipyrine were evaluated in this drug-drug interaction study. Twelve healthy male volunteers received three 200-mg capsules of antipyrine on days 1 and 22, and two 40-mg atorvastatin tablets in the morning on days ...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1996.tb04212.x
更新日期:1996-04-01 00:00:00
abstract::The Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), the German drug regulation authority, issued guidelines for determining whether bioavailability/bioequivalence studies are required for certain drugs. This decision tree is based on pharmacodynamic, pharmacokinetic, and physicochemical criteria. Details ...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1998.tb04385.x
更新日期:1998-10-01 00:00:00
abstract::Current dosing recommendations for rivaroxaban advocate dosage reduction in patients with moderate to severe renal impairment and avoidance of concomitant strong inhibitors of CYP3A or P-glycoprotein. However, rivaroxaban dosing in patients with mild renal impairment taking concomitant moderate inhibitors of CYP3A and...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/jcph.1044
更新日期:2018-04-01 00:00:00
abstract::Lemborexant is a novel orexin receptor antagonist approved in the United States and Japan for the treatment of insomnia. This article describes the population pharmacokinetics (PK) of lemborexant and the relationship of its daily steady-state exposure (Cav,ss ) to the probability of most frequent treatment-emergent ad...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/jcph.1683
更新日期:2020-12-01 00:00:00
abstract::Grapefruit is rich in flavonoids, which have been demonstrated to have a preventive influence on many chronic diseases, such as cancer and cardiovascular disease. However, since the early 1990s, the potential health benefits of grapefruit have been overshadowed by the possible risk of interactions between drugs and gr...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1177/0091270006294277
更新日期:2006-12-01 00:00:00
abstract::The pharmacokinetics (PK), pharmacodynamics (PD), and safety of a platelet GPIIb/IIIa receptor antagonist, RGD891, and its active metabolite, RGD039, were evaluated after administration of various intravenous regimens of RGD891 to healthy male volunteers in two Phase I studies. Plasma and urine concentrations of RGD89...
journal_title: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:2000-11-01 00:00:00
abstract::Therapeutic drug monitoring (TDM) has become standard clinical practice for gentamicin, amikacin, and vancomycin to optimize efficacy and reduce toxicity. TDM after the first dose of antibiotic was adopted in our institution. This study aims to evaluate if target therapeutic drug concentrations could be achieved more ...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/jcph.1509
更新日期:2020-01-01 00:00:00
abstract::Propafenone and its 5-hydroxy metabolite exhibit different electrophysiological properties. Objectives of the CAQ-PAF study were (1) to develop a strategy favoring propafenone instead of 5-hydroxypropafenone in plasma following oral administration of propafenone and (2) to evaluate the potential of low-dose quinidine ...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1177/0091270011399574
更新日期:2012-02-01 00:00:00
abstract::The aim of these two studies was to evaluate the safety and pharmacokinetics of oral nalmefene, a new orally effective opioid antagonist. In the first study, single ascending doses of 50, 100, 200, and 300 mg of nalmefene HCl were administered in double-blind fashion to four groups of healthy men. There were six subje...
journal_title:Journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1002/j.1552-4604.1987.tb02191.x
更新日期:1987-03-01 00:00:00
abstract::The pharmacokinetics and pharmacodynamics of verapamil were investigated in six chronic hemodialysis patients. A single oral 120-mg dose was administered both on a non-hemodialysis day and a hemodialysis day separated by greater than or equal to 7 days. Blood pressure and PR interval were measured simultaneously with ...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1988.tb03224.x
更新日期:1988-09-01 00:00:00
abstract::Health-related quality of life in people with intellectual disabilities can be affected by challenging behaviors and side effects of antipsychotics. The aim of this study was to evaluate the effect of discontinuation antipsychotic drugs on health-related quality of life, including data from 2 discontinuation trials: a...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/jcph.1311
更新日期:2019-02-01 00:00:00
abstract::Repaglinide is a novel insulin secretagogue developed in response to the need for a fast-acting, oral prandial glucose regulator for the treatment of type 2 (non-insulin-dependent) diabetes mellitus. Repaglinide is metabolized mainly in the liver; its pharmacokinetics may therefore be altered by hepatic dysfunction. T...
journal_title:Journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1177/00912700022008793
更新日期:2000-02-01 00:00:00
abstract::TAS-303 (4-piperidinyl 2,2-diphenyl-2-[propoxy-1,1,2,2,3,3,3-d7 ] acetate hydrochloride) is a novel selective noradrenaline reuptake inhibitor being developed for the treatment of stress urinary incontinence. An in vitro study and a physiologically based pharmacokinetic model simulation showed that TAS-303 had inhibit...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/jcph.1583
更新日期:2020-06-01 00:00:00
abstract::The alpha 1-adrenoceptor antagonists doxazosin and terazosin and the 5 alpha-reductase inhibitor finasteride are used in the treatment of benign prostatic hyperplasia. The aim of this study was to assess the potential pharmacokinetic interaction of doxazosin or terazosin when coadministered with finasteride. This was ...
journal_title:Journal of clinical pharmacology
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1177/009127009803801113
更新日期:1998-11-01 00:00:00
abstract::Psychoactive drugs are often widely used before tolerance and dependence is fully appreciated. Tolerance to cannabis-induced cardiovascular and autonomic changes, decreased intraocular pressure, sleep and sleep EEG, mood and behavioral changes is acquired and, to a great degree, lost rapidly with optimal conditions. M...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1981.tb02589.x
更新日期:1981-08-01 00:00:00
abstract::The influence of food on the bioavailability of trimoprostil , a new antiulcer prostaglandin E2 derivative, was investigated in healthy male volunteers in four separate studies. Doses of 0.75, 1.5, and 3.0 mg were administered orally in both the presence and absence of food followed by serial blood sampling through 24...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1984.tb01830.x
更新日期:1984-04-01 00:00:00
abstract::Thrombomodulin alfa is the recombinant extracellular domain of human thrombomodulin, which shows anticoagulation activity. To elucidate the pharmacokinetics of thrombomodulin alfa in patients with disseminated intravascular coagulation (DIC), population pharmacokinetic (PPK) analysis was performed using plasma concent...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1177/0091270010381900
更新日期:2011-09-01 00:00:00
abstract::A randomized, single-blind, placebo-controlled, parallel-group study was conducted to assess the effect of age and gender on the pharmacokinetics and pharmacodynamics of rivaroxaban - an oral, direct Factor Xa inhibitor. Subjects (n = 34) were enrolled into four groups: young males or females (aged 18-45 years) and el...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1002/jcph.5
更新日期:2013-03-01 00:00:00
abstract::Although alcohol consumption is involved in most acts of violence, most people do not become violent when they drink. Individuals also respond differently to alcohol on laboratory measures of aggression. The objective of this study was to determine whether individual differences in the effects of alcohol on a laborato...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1177/0091270004270457
更新日期:2005-01-01 00:00:00
abstract::Many astronauts experience intolerance to orthostatic stress after space flight, despite the ingestion of salt tablets and water equivalent to 0.9% saline just before their return to Earth. Previous research indicates that the ingestion of 1.07% saline solution increased plasma volume more than did 0.9% saline. Theref...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1994.tb04978.x
更新日期:1994-05-01 00:00:00
abstract::The effect of pomegranate juice (PJ) or grapefruit juice (GFJ) on CYP3A activity was studied in vitro and in healthy human volunteers. In human liver microsomes, the mean 50% inhibitory concentrations (IC(50)) for PJ and GFJ versus CYP3A (triazolam alpha-hydroxylation) were 0.61% and 0.55%, (v/v) respectively, without...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1177/0091270006298359
更新日期:2007-03-01 00:00:00
abstract::The availability of poisoning information from the pharmaceutical industry was evaluated. Manufacturers of the top 50 drugs were surveyed. Information that was received was classified by established criteria for evaluation. Compendia on poisoning information was evaluated based on 11 components ranging from toxicity i...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1979.tb02474.x
更新日期:1979-02-01 00:00:00
abstract::Optimal design has been used in the past mainly to optimize sampling schedules for clinical trials. Optimization on design variables other than sampling times has been published in the literature only once before. This study shows, as an example, optimization on the length of treatment periods to obtain reliable estim...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1177/0091270008329560
更新日期:2009-03-01 00:00:00
abstract::R(+)-alpha-lipoic acid is a natural occurring compound that acts as an essential cofactor for certain dehydrogenase complexes. The redox couple alpha-lipoic acid/dihydrolipoic acid possesses potent antioxidant activity. Exogenous racemic alpha-lipoic acid orally administered for the symptomatic treatment of diabetic p...
journal_title:Journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1177/0091270003258654
更新日期:2003-11-01 00:00:00
abstract::The present study was conducted to determine the absolute bioavailability of fimasartan (FMS; Kanarb(®) ) after the single oral administration of a 60-mg tablet or a single 30-mg intravenous (IV) infusion. This investigation was a randomized, single-dose, open-labeled, two-way crossover study of 16 healthy Korean male...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1002/jcph.618
更新日期:2016-05-01 00:00:00
abstract::Acute asthma exacerbations are primarily due to airway inflammation and remain one of the most frequent reasons for childhood hospitalizations. Although systemic corticosteroids remain the mainstay of therapy because of their anti-inflammatory properties, not all inflammatory pathways are responsive to systemic cortic...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/jcph.1738
更新日期:2021-03-01 00:00:00