Abstract:
:Hydroxymetabolites of the antidepressants nortriptyline and desipramine, like the parent drugs, inhibit neuronal uptake of noradrenaline (norepinephrine). In both plasma and cerebrospinal fluid (CSF), the concentrations of the 10-hydroxymetabolites of nortriptyline (10-OH-NT) are usually higher than those of the parent drugs, but there is a pronounced interindividual variation in the plasma concentrations. This shows that during treatment with nortriptyline, hydroxymetabolites exert, at least in some patients, major effects on brain noradrenaline neurons. Hydroxymetabolites of antidepressants are formed by the polymorphic cytochrome P450 enzyme CYP2D6. Nortriptyline is hydroxylated by this enzyme in a highly stereospecific way to the (-)-enantiomer of E-10-OH-NT. Among Caucasians, 7% are poor metabolisers of the CYP2D6 probe drug debrisoquine. These patients will form very little hydroxymetabolite. The affinity of E-10-OH-NT for muscarinic acetylcholine receptors in vitro was only one-eighteenth of the affinity of nortriptyline for these receptors. In healthy individuals, nortriptyline decreased saliva flow to a significantly greater extent than either E-10-OH-NT or placebo. In an ultrarapid hydroxylator of nortriptyline treated with very high doses of nortriptyline, the plasma concentration of unconjugated 10-OH-NT was very high without any sign of anticholinergic adverse effects. These results show that hydroxymetabolites of nortriptyline have much less anticholinergic effect than the parent drug. When racemic E-10-OH-NT per se was given to healthy individuals, the plasma concentration of the (-)-enantiomer was 5-fold higher than that of (+)-E-10-OH-NT. The 2 enantiomers were eliminated in parallel with an elimination half-life of 8 to 10 hours. A combined in vitro and in vivo investigation showed that a mean of 64% of (+)-E-10-OH-NT was glucuronidated in the liver and subsequently eliminated in urine. Of the administered (-)-enantiomer, a mean of 36% was eliminated as glucuronide formed in the intestine and 35% was actively secreted as unchanged form in urine. Plasma protein binding, determined by ultrafiltration, of the (+)- and (-)-enantiomers of E-10-OH-NT was 54 and 69%, respectively, which is less than that of nortriptyline (92%). The concentration of E-10-OH-NT in CSF was 50% of the concentration of unbound in plasma. There seems to be a stereoselective active transport of E-10-OH-NT from the CSF to blood. We administered racemic E-10-OH-NT to 5 patients during a major depressive episode.(ABSTRACT TRUNCATED AT 400 WORDS)
journal_name
Clin Pharmacokinetjournal_title
Clinical pharmacokineticsauthors
Nordin C,Bertilsson Ldoi
10.2165/00003088-199528010-00004subject
Has Abstractpub_date
1995-01-01 00:00:00pages
26-40issue
1eissn
0312-5963issn
1179-1926journal_volume
28pub_type
杂志文章,评审abstract::Since up to 90% of a theophylline dose is biotransformed, drugs influencing microsomal enzyme systems in the liver may affect the elimination of theophylline. Other integrated mechanisms (e.g. hepatic uptake) may also be altered by concurrent administration of other drugs. Whatever the mechanism, the interaction may b...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-198409040-00002
更新日期:1984-07-01 00:00:00
abstract:BACKGROUND:Olaparib is a first-in-class potent oral poly(ADP-ribose) polymerase inhibitor. OBJECTIVES:The aims of this analysis were to establish an integrated population pharmacokinetic (PK) model of olaparib in patients with solid tumors and to bridge the PK of olaparib between capsule and tablet formulations. METH...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,meta分析
doi:10.1007/s40262-018-0714-x
更新日期:2019-05-01 00:00:00
abstract:OBJECTIVE:To assess any pharmacokinetic interactions between loperamide and saquinavir. DESIGN:Double-blind, double-dummy, randomised, placebo-controlled, three-way crossover trial. PARTICIPANTS:Twelve healthy male and female volunteers, aged 24-46 years. METHODS:Saquinavir and loperamide pharmacokinetics were deter...
journal_title:Clinical pharmacokinetics
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.2165/00003088-200443140-00004
更新日期:2004-01-01 00:00:00
abstract::Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein cholesterol (LDL-C) by decreasing expression of the LDL receptor on hepatic cells. Evolocumab is a human monoclonal immunoglobulin G2 that binds specifically to human PCSK9 to reduce LDL-C. Evolocumab exhibits nonlinear kine...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.1007/s40262-017-0620-7
更新日期:2018-07-01 00:00:00
abstract::Aminoglycosides are important antibacterial agents for the treatment of serious infection. Evidence suggests that high peak plasma concentrations must be achieved early in the course of treatment if these agents are to be effective, but prolonged high concentrations may cause ototoxicity and nephrotoxicity. Peak plasm...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199427010-00004
更新日期:1994-07-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:Losmapimod is an orally available, potent p38 mitogen-activated protein kinase inhibitor. It is in development as an anti-inflammatory drug in different therapeutic areas. Clinical studies have shown that losmapimod is well tolerated and safe in humans and several studies have shown its pharmac...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,随机对照试验
doi:10.1007/s40262-012-0025-6
更新日期:2013-03-01 00:00:00
abstract::Sevoflurane is a comparatively recent addition to the range of inhalational anaesthetics which has been recently released for clinical use. In comparison to older inhalational agents such as isoflurane or halothane, the most important property of sevoflurane is its low solubility in the blood. This results in a more r...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199936010-00002
更新日期:1999-01-01 00:00:00
abstract::The relative bioavailability of a single oral dose of temafloxacin given with and without enteral feeding was determined in 18 healthy male volunteers in a randomised crossover study. Subjects were administered 600mg of temafloxacin orally as an intact tablet, or a crushed tablet suspended in water administered throug...
journal_title:Clinical pharmacokinetics
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.2165/00003088-199200221-00008
更新日期:1992-01-01 00:00:00
abstract:OBJECTIVE:To study the pharmacokinetics of micafungin in intensive care patients and assess pharmacokinetic (PK) target attainment for various dosing strategies. METHODS:Micafungin PK data from 20 intensive care unit patients were available. A population-PK model was developed. Various dosing regimens were simulated: ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-017-0509-5
更新日期:2017-10-01 00:00:00
abstract::Platelets contribute significantly to arterial-occlusive thrombosis, one of the major causes of death and disease throughout the world. Consequently, inhibiting platelet function is a potentially important therapeutic goal. Among agents that inhibit platelet function, ticlopidine shows a wide spectrum of antiplatelet ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199426050-00003
更新日期:1994-05-01 00:00:00
abstract:BACKGROUND:Tildrakizumab is an anti-interleukin-23p19 monoclonal antibody recently approved for the treatment of chronic plaque psoriasis. METHODS:This analysis characterizes the population pharmacokinetics of subcutaneous tildrakizumab and identifies covariates influencing exposure in 2098 healthy volunteers and subj...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,随机对照试验
doi:10.1007/s40262-019-00743-7
更新日期:2019-08-01 00:00:00
abstract::Lignocaine is widely used as a local anaesthetic and antiarrhythmic drug. It is commonly administered to patients with acute myocardial infarction as prophylaxis for ventricular fibrillation, although its efficacy in preventing primary ventricular fibrillation is still debated. Toxicity, sometimes with serious clinica...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-197803030-00001
更新日期:1978-05-01 00:00:00
abstract::Aminoglycoside antibiotics are very important in the treatment of Gram-negative infections and as synergistic agents for the treatment of staphylococcal and streptococcal (group B streptococci and enterococci) infections. However, these agents have a narrow therapeutic index. Thus, a number of new antibiotics have bee...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199426010-00006
更新日期:1994-01-01 00:00:00
abstract::Antipyrine pharmacokinetics were studied in 6 healthy women before and 2, 8 and 12 weeks after administering the injectable progestagen (progestin), norethisterone (norethindrone) enanthate 200mg intramuscularly. Additionally, antipyrine kinetics in 5 women who had previously used the injectable contraceptive for 8 to...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-198611020-00007
更新日期:1986-03-01 00:00:00
abstract:BACKGROUND:Duloxetine, a selective serotonin (5-hydroxytryptamine) and norepinephrine reuptake inhibitor, has been approved since 2004 for the treatment of adults with major depressive disorder (MDD). It is currently not approved for use in pediatric patients (aged <18 years) with MDD. The clinical development program ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-014-0149-y
更新日期:2014-08-01 00:00:00
abstract::A substantial proportion of migraine patients have gastric stasis and suffer severe nausea and/or vomiting during their migraine attack. This may lead to erratic absorption from the gastrointestinal tract and make oral treatment unsatisfactory. For such patients, an intranasal formulation may be advantageous. Sumatrip...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-200241110-00002
更新日期:2002-01-01 00:00:00
abstract::Cancer chemotherapy doses are empirical in that the majority are administered at a fixed dose (mg/m2 or mg/kg). One reason for this is the intrinsic sensitivity of the tumour or host cells to one particular chemotherapy agent is unknown. Therefore, the likelihood of response or toxicity is unpredictable a priori. This...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199732040-00005
更新日期:1997-04-01 00:00:00
abstract::Pancuronium is frequently used in coronary artery surgery, but its pharmacokinetics in these patients are still unknown. It is possible that dopamine, administered to prevent renal impairment induced by the surgery, might promote the elimination of pancuronium. Therefore, the pharmacokinetics of a bolus dose of pancur...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-199019060-00005
更新日期:1990-12-01 00:00:00
abstract::Analogues of human insulin have been developed to more closely replicate the physiology of meal-related and basal insulin secretion. Three rapid-acting analogues and two basal analogues are available for clinical use. Insulin aspart and insulin lispro have nearly identical pharmacokinetic and pharmacodynamic profiles ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-200847090-00003
更新日期:2008-01-01 00:00:00
abstract::The pharmacokinetics of dothiepin were evaluated in 9 depressed patients following a single oral dose of 75 mg. Blood and plasma concentrations of dothiepin and 2 major metabolites, northiaden and dothiepin S-oxide, were measured by gas chromatography/mass fragmentography. The mean (+/-SD) peak plasma concentrations o...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-198308020-00004
更新日期:1983-03-01 00:00:00
abstract::5-Fluorouracil, first introduced as a rationally synthesized anticancer agent 30 years ago, continues to be widely used in the management of several common malignancies including cancer of the colon, breast and skin. This drug, an analogue of the naturally occurring pyrimidine uracil, is metabolised via the same metab...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-198916040-00002
更新日期:1989-04-01 00:00:00
abstract::Pharmacokinetic parameters of third generation cephalosporins vary widely, requiring different dosage regimens and adjustment methods for each agent. Although their antibacterial spectrum favours their usage in infections caused by aerobic Gram-negative organisms, due to their limited post-antibiotic effect against th...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199222020-00004
更新日期:1992-02-01 00:00:00
abstract::The critically ill patient occupies an increasing amount of time and bed space in modern hospital practice, and also commands increasing expenditure. Drug therapy in these patients has, in the past, been based on data derived from healthy volunteers, fit anaesthetised patients undergoing minor operative procedures, or...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-198814060-00003
更新日期:1988-06-01 00:00:00
abstract::Population pharmacokinetic and pharmacodynamic analysis is an important tool to support optimal treatment in clinical oncology. The population approach is suitable to explain variability between patients and to establish relationships between drug exposure and a relevant pharmacodynamic parameter. This can facilitate ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-200847080-00001
更新日期:2008-01-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:Escitalopram is one of the most commonly prescribed selective serotonin reuptake inhibitors (SSRIs). It is thought to act by blocking the serotonin transporter (SERT). However, its dose-SERT occupancy relationship is not well known, so it is not clear what level of SERT blockade is achieved by ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-016-0444-x
更新日期:2017-04-01 00:00:00
abstract:BACKGROUND:Lorazepam is one of the preferred agents used for intravenous treatment of status epilepticus (SE). We combined data from two pediatric clinical trials to characterize the population pharmacokinetics of intravenous lorazepam in infants and children aged 3 months to 17 years with active SE or a history of SE....
journal_title:Clinical pharmacokinetics
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1007/s40262-016-0486-0
更新日期:2017-08-01 00:00:00
abstract:BACKGROUND:Recombinant methionyl human leptin (r-metHuLeptin) has demonstrated efficacy in improving hormonal and metabolic parameters in leptin-deficient states, and it has been suggested that leptin replacement may reverse metabolic adaptations during weight loss interventions. The pharmacokinetics of subcutaneously ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-200847110-00006
更新日期:2008-01-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:This study proposes a model-informed approach for therapeutic drug monitoring (TDM) of rifampicin to improve tuberculosis (TB) treatment. METHODS:Two datasets from pulmonary TB patients were used: a pharmacokinetic study (34 patients, 373 samples), and TDM data (96 patients, 391 samples) colle...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-018-00732-2
更新日期:2019-06-01 00:00:00
abstract::The effects of anaesthesia and surgery on the pharmacokinetics of ketobemidone were studied in 12 patients. Plasma ketobemidone concentrations were assayed with a mass-fragmentographic method. The peroperative Vd(area) was 5.9 +/- 2.6L/kg and the terminal half-life was 3.9 +/- 1.7 h. In the postoperative period Vd(are...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-198207030-00005
更新日期:1982-05-01 00:00:00
abstract::The importance of in-depth knowledge about the pharmacokinetics of a drug is evident because pharmacokinetic behaviour may correlate with activity and toxicity. The most elaborate pharmacokinetic investigation is a so-called mass balance study employing a radioactive tracer. A mass balance study investigates the plasm...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-200645010-00003
更新日期:2006-01-01 00:00:00