Review of UCN-01 development: a lesson in the importance of clinical pharmacology.

Abstract:

:UCN-01 is a protein kinase inhibitor under development as a novel anticancer drug. The initial pharmacologic features in patients were not predicted from preclinical experiments. The distribution volume and the systemic clearance were much lower than those in experimental animals (mice, rats, and dogs), and the elimination half-life was unusually long (>200 hours). The unbound fraction in human plasma was also much smaller than that in dogs, rats and mice, as was the binding of UCN-01 to human alpha-1 acid glycoprotein much stronger than that to human serum albumin or human gamma-globulin. The association constants for alpha-1 acid glycoprotein and human plasma were approximately 8 x 10(8)(mol/L)(-1), indicating extremely high affinity. In this review article, the authors discuss the pharmacologic features of UCN-01 across species and provide a perspective on how this information could be applied prospectively to the future development of this agent.

journal_name

J Clin Pharmacol

authors

Fuse E,Kuwabara T,Sparreboom A,Sausville EA,Figg WD

doi

10.1177/0091270005274549

subject

Has Abstract

pub_date

2005-04-01 00:00:00

pages

394-403

issue

4

eissn

0091-2700

issn

1552-4604

pii

45/4/394

journal_volume

45

pub_type

杂志文章,评审
  • Pharmacokinetics and pharmacodynamics of ranitidine in neonates treated with extracorporeal membrane oxygenation.

    abstract::The pharmacokinetics and pharmacodynamics of ranitidine were studied in 13 term neonates with stable renal and hepatic function who were treated with extracorporeal membrane oxygenation (ECMO). Ranitidine was initially administered as a single 2 mg/kg dose over 10 minutes and intragastric pH was monitored to determine...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章

    doi:10.1002/j.1552-4604.1998.tb04443.x

    authors: Wells TG,Heulitt MJ,Taylor BJ,Fasules JW,Kearns GL

    更新日期:1998-05-01 00:00:00

  • Effect of faldaprevir on raltegravir pharmacokinetics in healthy volunteers.

    abstract::Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor and an inhibitor of UDP-glucuronosyltransferase-1A1 (UGT1A1), which is involved in raltegravir clearance. Raltegravir, an HIV integrase inhibitor, may be used in combination with HCV treatment in HCV/HIV co-infected patients. In this open-label,...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/jcph.418

    authors: Joseph D,Rose P,Strelkowa N,Schultz A,Garcia J,Elgadi M,Huang F

    更新日期:2015-04-01 00:00:00

  • The relevance of T-type calcium antagonists: a profile of mibefradil.

    abstract::L- and T-type voltage-dependent transmembrane calcium channels are important for normal functioning of the cardiovascular system. T-type channels are a heterogeneous group, and have physiologic and pathophysiologic relevance in a number of organ systems, including the heart and central nervous system. They appear to b...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,评审

    doi:10.1002/j.1552-4604.1998.tb04804.x

    authors: Glasser SP

    更新日期:1998-08-01 00:00:00

  • Comparison of sustained-release quinidines given twice daily to patients with ventricular ectopy.

    abstract::To compare the steady-state kinetic profiles and ectopy-suppression rates of two sustained-release forms of quinidine with those of a conventional quinidine preparation, 18 patients with ventricular ectopy were studied in randomized crossover fashion. The drugs were conventional quinidine sulfate 300 mg q6h, sustained...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1002/j.1552-4604.1986.tb02956.x

    authors: Lehmann CR,Boran KJ,Kruyer WB,Van Reet RE,Scoville GS,Pierson WP,Melikian AP,Crowe JT,Wright GJ

    更新日期:1986-11-01 00:00:00

  • Tecarfarin, a novel vitamin K reductase antagonist, is not affected by CYP2C9 and CYP3A4 inhibition following concomitant administration of fluconazole in healthy participants.

    abstract::Comparative pharmacokinetics of vitamin K epoxide reductase antagonists tecarfarin and warfarin were assessed before and after coadministration for 21 days of the CYP450 inhibitor fluconazole in a randomized, open-label, single-center drug interaction study. Twenty healthy adult participants were randomized 1:1 to rec...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,随机对照试验

    doi:10.1177/0091270010370588

    authors: Bavisotto LM,Ellis DJ,Milner PG,Combs DL,Irwin I,Canafax DM

    更新日期:2011-04-01 00:00:00

  • Changes in total body water during spaceflight.

    abstract::This experiment represents the first time that it has been possible to measure a body fluid compartment by direct means during spaceflight. Based on the results observed in the five crewmen in this study, it is concluded that TBW decreases by 3.4% after 1 to 3 days of exposure to microgravity in the Space Shuttle. Som...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1991.tb03663.x

    authors: Leach CS,Inners LD,Charles JB

    更新日期:1991-10-01 00:00:00

  • Saturable first-pass kinetics of propranolol.

    abstract::Reduced bioavailability (F) due to hepatic first-pass extraction of an oral dose (D) is a well-known pharmacokinetic phenomenon. An integrated solution for Michaelis-Menten kinetics of the first-pass effect is derived from the maximal metabolic rate (Vm), volume of distribution (Vd), first order absorption rate consta...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1989.tb03320.x

    authors: Keller F,Kunzendorf U,Walz G,Haller H,Offermann G

    更新日期:1989-03-01 00:00:00

  • Coadministration of acetaminophen and troglitazone: pharmacokinetics and safety.

    abstract::Troglitazone, a PPAR-gamma agonist, enhances the actions of insulin on muscle and liver. It is metabolized predominantly in the liver to a sulfate conjugate and a quinone metabolite. Acetaminophen also undergoes metabolism by conjugation. This three-way crossover study in 12 healthy male volunteers was conducted to in...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:

    authors: Young MA,Lettis S,Eastmond R

    更新日期:1998-09-01 00:00:00

  • A Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for Bococizumab, a Humanized Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, and Its Application in Early Clinical Development.

    abstract::Bococizumab (RN316/PF-04950615), a humanized monoclonal antibody, binds to secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) and prevents its downregulation of low-density lipoprotein receptor, leading to improved clearance and reduction of low-density lipoprotein cholesterol (LDL-C) in plasma. A mechanis...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/jcph.867

    authors: Udata C,Garzone PD,Gumbiner B,Joh T,Liang H,Liao KH,Williams JH,Meng X

    更新日期:2017-07-01 00:00:00

  • Interaction trial between artemether-lumefantrine (Riamet) and quinine in healthy subjects.

    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

    authors: Lefèvre G,Carpenter P,Souppart C,Schmidli H,Martin JM,Lane A,Ward C,Amakye D

    更新日期:2002-10-01 00:00:00

  • An integrated glucose-insulin model to describe oral glucose tolerance test data in healthy volunteers.

    abstract::The extension of the previously developed integrated models for glucose and insulin (IGI) to include the oral glucose tolerance test (OGTT) in healthy volunteers could be valuable to better understand the differences between healthy individuals and those with type 2 diabetes mellitus (T2DM). Data from an OGTT in 23 he...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1177/0091270009341185

    authors: Silber HE,Frey N,Karlsson MO

    更新日期:2010-03-01 00:00:00

  • Changes in Health-Related Quality of Life in People With Intellectual Disabilities Who Discontinue Long-Term Used Antipsychotic Drugs for Challenging Behaviors.

    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

    authors: Ramerman L,Hoekstra PJ,de Kuijper G

    更新日期:2019-02-01 00:00:00

  • Once-daily verapamil in the treatment of mild-to-moderate hypertension: a double-blind placebo-controlled dose-ranging study.

    abstract::Supine office blood pressures (SOBP) and 24-hour automated ambulatory blood pressure monitorings (AABPM) showed blood pressure reductions from a stable baseline to active treatment with 120-, 240-, and 480-mg doses of a new verapamil QD capsule (solid-spheroidal-oral once-daily drug-absorption system: (SODAS) in patie...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1002/j.1552-4604.1991.tb03698.x

    authors: Carr AA,Bottini PB,Prisant LM,Fisher LD,Devane JG,O'Brien DE,Rhoades RB

    更新日期:1991-02-01 00:00:00

  • Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitus.

    abstract::This study was conducted to assess the effect of noninsulin-dependent diabetes mellitus (NIDDM) and gender on the pharmacokinetics of metformin and to investigate whether or not metformin exhibits dose-dependent pharmacokinetics. The pharmacodynamic effects (on plasma glucose and insulin) of metformin in patients with...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1177/009127009603601105

    authors: Sambol NC,Chiang J,O'Conner M,Liu CY,Lin ET,Goodman AM,Benet LZ,Karam JH

    更新日期:1996-11-01 00:00:00

  • The novel therapeutic implications of azlocillin's dose-dependent pharmacokinetics: contributing physiologic mechanisms and a prospective, cross-over designed trial.

    abstract::Azlocillin is an important acylureido penicillin antibiotic for the management of complex gram-negative infections particularly those caused by Pseudomonas species. The current studies demonstrate that it manifests dose-dependent pharmacokinetics during the usual regimens of clinical dosing, that enterohepatic recircu...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1002/j.1552-4604.1987.tb03055.x

    authors: Whelton A,Stout RL,Spilman PS,Delgado FA,Watson AJ

    更新日期:1987-07-01 00:00:00

  • Pomegranate juice does not impair clearance of oral or intravenous midazolam, a probe for cytochrome P450-3A activity: comparison with grapefruit juice.

    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

    authors: Farkas D,Oleson LE,Zhao Y,Harmatz JS,Zinny MA,Court MH,Greenblatt DJ

    更新日期:2007-03-01 00:00:00

  • The absolute bioavailability of oral melatonin.

    abstract::The absolute bioavailability of oral melatonin tablets was studied in 12 normal healthy volunteers. Subjects were administered, in a randomized crossover fashion, melatonin 2 mg intravenously and 2 and 4 mg orally. Blood was sampled over approximately eight (estimated) half-lives. Both the 2 and the 4 mg oral dosages ...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1177/00912700022009422

    authors: DeMuro RL,Nafziger AN,Blask DE,Menhinick AM,Bertino JS Jr

    更新日期:2000-07-01 00:00:00

  • Expression of six drug transporters in vaginal, cervical, and colorectal tissues: Implications for drug disposition in HIV prevention.

    abstract::Effective antiretroviral (ARV)-based HIV prevention strategies require optimizing drug exposure in mucosal tissues; yet factors influencing mucosal tissue disposition remain unknown. We hypothesized drug transporter expression in vaginal, cervical, and colorectal tissues is a contributing factor and selected 3 efflux ...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/jcph.248

    authors: Nicol MR,Fedoriw Y,Mathews M,Prince HM,Patterson KB,Geller E,Mollan K,Mathews S,Kroetz DL,Kashuba AD

    更新日期:2014-05-01 00:00:00

  • A placebo-controlled comparative evaluation of diclofenac dispersible versus ibuprofen in postoperative pain after third molar surgery.

    abstract::The analgesic efficacy of single oral doses of drinkable diclofenac dispersible 50 mg was compared with that of ibuprofen 400 mg and placebo in a randomized, double-blind, parallel-group trial in 257 adult patients (245 valid for efficacy) with severe postoperative pain after extraction of an impacted lower third mola...

    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:10.1002/j.1552-4604.1994.tb03990.x

    authors: Bakshi R,Frenkel G,Dietlein G,Meurer-Witt B,Schneider B,Sinterhauf U

    更新日期:1994-03-01 00:00:00

  • Optimal Designs for Model-Based Assessment of Insulin Sensitivity and Glucose Effectiveness.

    abstract::The integrated minimal model allows assessment of clinical diagnosis indices, for example, insulin sensitivity (SI ) and glucose effectiveness (SG ), from data of the insulin-modified intravenous glucose tolerance test (IVGTT), which is laborious with an intense sampling schedule, up to 32 samples. The aim of this stu...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/jcph.1707

    authors: Ibrahim MMA,Redestad E,Kjellsson MC

    更新日期:2021-01-01 00:00:00

  • Significance of classifying antiarrhythmic actions since the cardiac arrhythmia suppression trial.

    abstract::The Cardiac Antiarrhythmic Suppression Trial (CAST) showed flecainide and encainide induced excess mortality compared with placebo. Labeling drugs as Class 1C is based on clinical observations, comprising measurements of the electrocardiographic parameters QRS. H-V and J-T intervals and of effective refractory period ...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,评审

    doi:10.1002/j.1552-4604.1991.tb03695.x

    authors: Vaughan Williams EM

    更新日期:1991-02-01 00:00:00

  • A review of potential cardiovascular uses of intravenous glucagon administration.

    abstract::Glucagon is a counter-regulatory hormone that is classically used to treat hypoglycemia. However, it can elicit the generation of cAMP within the myocardium to cause positive inotropic and chronotropic effects without the need for beta-1 adrenoceptor stimulation. Glucagon has been used extensively to treat beta-blocke...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,评审

    doi:

    authors: White CM

    更新日期:1999-05-01 00:00:00

  • Effects of protriptyline and perphenazine in neurotic depressed outpatients.

    abstract::A four-week comparison of protriptyline 10 mg three times a day and perphenazine 2 mg three times a day, alone and in combination, and a placebo in a group of nonpsychotic depressed outpatients showed no significant differences among any of the treatment groups after both two and four weeks, and a slight trend in favo...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章

    doi:10.1002/j.1552-4604.1975.tb02382.x

    authors: Weinstock R,Fisher S,Spillane J,Ise C,Shaw D,Torop P

    更新日期:1975-08-01 00:00:00

  • Cardiovascular effects of H2-receptor antagonists.

    abstract::The type II histamine receptor antagonists, cimetidine and ranitidine, widely used in treatment of peptic ulcer disease have been reported to cause bradycardia. To evaluate the cardiovascular effects of H2 antagonists nineteen healthy volunteers were entered into a double-blind crossover comparison of cimetidine 300 m...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章

    doi:10.1002/j.1552-4604.1989.tb03365.x

    authors: Hughes DG,Dowling EA,DeMeersman RE,Garnett WR,Karnes HT

    更新日期:1989-05-01 00:00:00

  • A pharmacodynamic and pharmacokinetic comparison of intravenous quinaprilat and oral quinapril.

    abstract::Quinaprilat is the active metabolite of quinapril, an orally active angiotensin-converting enzyme (ACE) inhibitor. The dose-response and duration-of-effect after single intravenous doses of quinaprilat and placebo (part A) and after administration of oral quinapril solution and intravenous quinaprilat (part B) were as...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1002/j.1552-4604.1996.tb05028.x

    authors: Breslin E,Posvar E,Neub M,Trenk D,Jahnchen E

    更新日期:1996-05-01 00:00:00

  • Influence of food on the bioavailability of trimoprostil: an overview.

    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

    authors: Wills RJ

    更新日期:1984-04-01 00:00:00

  • Effects of Corydalis yanhusuo and Angelicae dahuricae on cold pressor-induced pain in humans: a controlled trial.

    abstract::Pain is considered the most common complaint worldwide for which patients seek treatment. Conventional analgesic agents play an important role in modern pain therapy, but they cause several adverse effects. Therefore, newer and better analgesics continue to be investigated. In this controlled clinical trial, the autho...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章

    doi:10.1177/0091270004267809

    authors: Yuan CS,Mehendale SR,Wang CZ,Aung HH,Jiang T,Guan X,Shoyama Y

    更新日期:2004-11-01 00:00:00

  • Relationships of Changes in Pharmacokinetic Parameters of Substrate Drugs in Drug-Drug Interactions on Metabolizing Enzymes and Transporters.

    abstract::A general objective of drug-drug interaction (DDI) studies is to determine whether potential interactions of new molecular entities with concomitantly administered other drugs exist and, if DDIs occur, whether dosage adjustments are required. A typical end point for DDI evaluations is the ratio of area under the plasm...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/jcph.1104

    authors: Yamazaki S

    更新日期:2018-08-01 00:00:00

  • Model-Based Selection and Recommendation for Subcutaneous Abatacept Dose in Patients With Polyarticular Juvenile Idiopathic Arthritis.

    abstract::The selective T-cell costimulation modulator abatacept is approved for treatment of adult rheumatoid arthritis (RA) and polyarticular juvenile idiopathic arthritis (pJIA; 6-17 years [intravenous] and 2-17 years [subcutaneous]). An extrapolation approach was taken to determine subcutaneous weight-tiered doses of abatac...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/jcph.1797

    authors: Gandhi Y,Passarell JA,Roy A,Murthy B

    更新日期:2020-12-07 00:00:00

  • The effects of epoprostenol on drug disposition. II: A pilot study of the pharmacokinetics of furosemide with and without epoprostenol in patients with congestive heart failure.

    abstract::The effect of epoprostenol on the pharmacokinetics of furosemide was investigated in 23 patients with end-stage congestive heart failure (CHF) receiving conventional therapy alone or conventional therapy plus epoprostenol. Estimates of the apparent oral clearance, volume of distribution, and absorption rate constant f...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章

    doi:10.1002/j.1552-4604.1996.tb04196.x

    authors: Carlton LD,Patterson JH,Mattson CN,Schmith VD

    更新日期:1996-03-01 00:00:00