Human drug metabolism and the cytochromes P450: application and relevance of in vitro models.

Abstract:

:The cytochromes P450 (CYPs) constitute a superfamily of hemoprotein enzymes that are responsible for the biotransformation of numerous xenobiotics, including therapeutic agents. Studies of the biochemical and enzymatic properties of these enzymes and their molecular genetics and regulation of gene expression and activity have greatly enhanced our understanding of several aspects of clinical pharmacology such as pharmacokinetic variability, drug toxicity, and drug interactions. This review evaluates the major human hepatic drug-metabolizing CYP enzymes and their clinically relevant substrates, inhibitors, and inducers. Also discussed are the molecular bases and clinical implications of genetic polymorphisms that affect the CYPs. Much of the information on the specificity of substrates and inhibitors of the CYP enzymes is derived from in vitro studies using human liver microsomes and heterologously expressed CYP enzymes. These methods are discussed, and guidelines are provided for designing enzyme kinetic and reaction phenotyping studies using multiple approaches. The strengths, weaknesses, and discrepancies among the different approaches are considered using representative examples. The mathematical models used in predicting the pharmacokinetic clearance of a drug from in vitro estimates of intrinsic clearance and the principles of quantitative in vitro-in vivo scaling of metabolic drug interactions are also discussed.

journal_name

J Clin Pharmacol

authors

Venkatakrishnan K,Von Moltke LL,Greenblatt DJ

doi

10.1177/00912700122012724

subject

Has Abstract

pub_date

2001-11-01 00:00:00

pages

1149-79

issue

11

eissn

0091-2700

issn

1552-4604

journal_volume

41

pub_type

杂志文章,评审
  • Anti-IL21 receptor monoclonal antibody (ATR-107): Safety, pharmacokinetics, and pharmacodynamic evaluation in healthy volunteers: a phase I, first-in-human study.

    abstract::Safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ATR-107, a fully human monoclonal anti-IL-21 receptor (IL-21R) antibody, administered as ascending single doses, subcutaneously or intravenously, was evaluated in a placebo-controlled, double-blind trial in healthy subjects. The dose levels were...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,多中心研究

    doi:10.1002/jcph.158

    authors: Hua F,Comer GM,Stockert L,Jin B,Nowak J,Pleasic-Williams S,Wunderlich D,Cheng J,Beebe JS

    更新日期:2014-01-01 00:00:00

  • Clonidine clearance matures rapidly during the early postnatal period: a population pharmacokinetic analysis in newborns with neonatal abstinence syndrome.

    abstract::The population pharmacokinetic (PK) profile of oral clonidine was characterized in newborns with neonatal abstinence syndrome, and significant covariates affecting its PK parameters were identified. Plasma clonidine concentration data were obtained from a clinical trial in which 36 newborns, aged 1 to 25 days (postnat...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1177/0091270010370587

    authors: Xie HG,Cao YJ,Gauda EB,Agthe AG,Hendrix CW,Lee H

    更新日期:2011-04-01 00:00:00

  • Pharmacokinetics and pharmacodynamics of figitumumab, a monoclonal antibody targeting the insulin-like growth factor 1 receptor, in healthy participants.

    abstract::This study determined the pharmacokinetics (PK) of figitumumab and its effects on insulin-like growth factor (IGF) axis-related biomarkers, following a single intravenous dose (10 [n = 16] and 20 [n = 12] mg/kg) in healthy adults. Serial blood sampling for PK and biomarkers was conducted up to 84 days postdose. A dose...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1177/0091270011432934

    authors: Yin D,Sleight B,Alvey C,Hansson AG,Bello A

    更新日期:2013-01-01 00:00:00

  • Third generation cephalosporins: safety profiles after 10 years of clinical use.

    abstract::Compared with aminoglycosides, chloramphenicol, sulfonamides, tetracyclines, and even penicillins, the cephalosporins represent a remarkably safe class of antibiotics. Among the cephalosporins, the extended spectrum, third generation agents developed generally produce few side effects and appear to be less allergenic ...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,评审

    doi:10.1002/j.1552-4604.1990.tb03476.x

    authors: Neu HC

    更新日期:1990-05-01 00:00:00

  • Guidelines for antiinflammatory drug research.

    abstract::Guidelines have been developed by the Bureau of Drugs, FDA, for antinflammatory drug development. They address the problem of efficacy and safety testing but leave the definition of qualified investigators and appropriate subjects unstated. The natural history of rheumatoid arthritis, the most-studied chronic inflamma...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章

    doi:10.1002/j.1552-4604.1977.tb01544.x

    authors: Ehrlich GE

    更新日期:1977-11-01 00:00:00

  • Pentopril-cimetidine interaction caused by a reduction in hepatic blood flow.

    abstract::The interactive effects of the coadministration of steady-state cimetidine and single-dose pentopril, an angiotensin converting enzyme inhibitor, on the pharmacokinetic disposition of each other were studied in humans. Cimetidine reduced the clearance of pentopril by 11 to 14%. This reduction in clearance was shown to...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1988.tb03136.x

    authors: Kochak GM,Rakhit A,Thompson TN,Hurley ME

    更新日期:1988-03-01 00:00:00

  • Cerebral blood flow velocities by transcranial Doppler during parabolic flight.

    abstract::Microgravity is produced for 20 to 30 seconds in NASA's KC-135 aircraft at the end of a 2 G pullup for each of 40 parabolas per flight. Continuous transcranial Doppler ultrasound, arterial blood pressure, and acceleration levels were recorded for 12 male and 8 female healthy subjects without known cardiovascular or ce...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1991.tb03648.x

    authors: Bondar RL,Stein F,Kassam MS,Dunphy PT,Bennett BS,Johnston KW

    更新日期:1991-10-01 00:00:00

  • Pharmacokinetics, pharmacodynamics, and safety of peginterferon beta-1a in subjects with normal or impaired renal function.

    abstract::Peginterferon beta-1a was efficacious in a Phase 3 relapsing multiple sclerosis trial, and its safety profile was consistent with other beta interferons. This study evaluated the impact of renal impairment on the pharmacokinetics and pharmacodynamics (neopterin elevation; a biomarker of pharmacological activity induce...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,多中心研究

    doi:10.1002/jcph.390

    authors: Hu X,Seddighzadeh A,Stecher S,Zhu Y,Goyal J,Matson M,Marbury T,Smith W,Nestorov I,Hung S

    更新日期:2015-02-01 00:00:00

  • Adverse effects of commonly ordered oral narcotics.

    abstract::Approximately equianalgesic oral doses of codeine, an oxycodone compound resembling Percodan, and pentazocine were compared for adverse effects in a double-blind, randomized study of four doses of each drug given over two days to 247 postsurgical patients with pain. Placebo and parenteral morphine were also treated 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.1552-4604.1981.tb01724.x

    authors: Kantor TG,Hopper M,Laska E

    更新日期:1981-01-01 00:00:00

  • Investigation of safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of a long-acting α-MSH analog in healthy overweight and obese subjects.

    abstract::MC4-NN2-0453 is a novel, long-acting, selective, melanocortin-4-receptor agonist developed for treatment of obesity. This first-human-dose, randomized, double-blind, placebo-controlled trial investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of MC4-NN2-0453 in ov...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,随机对照试验

    doi:10.1002/jcph.211

    authors: Royalty JE,Konradsen G,Eskerod O,Wulff BS,Hansen BS

    更新日期:2014-04-01 00:00:00

  • Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms.

    abstract::Interethnic variability in pharmacokinetics can cause unexpected outcomes such as therapeutic failure, adverse effects, and toxicity in subjects of different ethnic origin undergoing medical treatment. It is important to realize that both genetic and environmental factors can lead to these differences among ethnic gro...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,评审

    doi:10.1177/0091270004268128

    authors: Kim K,Johnson JA,Derendorf H

    更新日期:2004-10-01 00:00:00

  • Nalmefene: safety and kinetics after single and multiple oral doses of a new opioid antagonist.

    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

    authors: Dixon R,Gentile J,Hsu HB,Hsiao J,Howes J,Garg D,Weidler D

    更新日期:1987-03-01 00:00:00

  • The influence of intravenous cimetidine dosage regimens on the disposition of theophylline.

    abstract::The influence of the method of cimetidine administration on theophylline disposition was studied in nine healthy, cigarette smoking male volunteers. The treatment phases consisted of: A) theophylline alone, B) theophylline plus intermittent cimetidine therapy (300 mg IV every 6 hr), and C) theophylline in combination ...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1989.tb03398.x

    authors: Gutfeld MB,Welage LS,Walawander CA,Wilton JH,Harrison NJ

    更新日期:1989-07-01 00:00:00

  • Ovulation-inhibiting effects of dienogest in a randomized, dose-controlled pharmacodynamic trial of healthy women.

    abstract::Dienogest offers pharmacological advantages for the effective treatment of endometriosis and for use in contraception and hormone replacement therapy. This pharmacodynamic study investigated the ovulation-inhibiting effects of dienogest monotherapy in healthy women. Dienogest was administered at 0.5, 1, 2, or 3 mg dai...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,随机对照试验

    doi:10.1177/0091270011423664

    authors: Klipping C,Duijkers I,Remmers A,Faustmann T,Zurth C,Klein S,Schuett B

    更新日期:2012-11-01 00:00:00

  • Clinical microdialysis in skin and soft tissues: an update.

    abstract::Traditionally, plasma or serum drug concentrations have been used for the assessment of bioavailability and bioequivalence. Since in the majority of cases the site of drug action is in the tissue rather than the blood, the use of corresponding free, unbound concentrations in the tissue is a much more meaningful approa...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,评审

    doi:10.1177/0091270007312152

    authors: Schmidt S,Banks R,Kumar V,Rand KH,Derendorf H

    更新日期:2008-03-01 00:00:00

  • Safety and tolerability of single intravenous doses of T cell modulatory peptide (TCMP-80) in healthy volunteers.

    abstract::T Cell Modulatory Peptide (TCMP-80), L-lysine-L-serine, is a synthetic dipeptide structurally related to a selected amino acid sequence in human immunoglobulin G. Based on in vitro and preclinical in vivo testing, TCMP-80 has immunomodulatory properties. This report describes the first administration of TCMP-80 to man...

    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.1552-4604.1990.tb03605.x

    authors: Eldon MA,Smith RA,Leese PT,Daigle AE,Katz DV,Richieri SP

    更新日期:1990-04-01 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

  • Enalapril in the management of hypertension associated with renal artery stenosis.

    abstract::Enalapril maleate (MK-421) is a new non-sulfhydryl-containing converting-enzyme inhibitor that has been shown to be effective and well tolerated in patients with essential hypertension. Data on its effectiveness and safety in patients with renovascular hypertension are limited and have involved predominantly short-ter...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1177/009127008702700105

    authors: Canzanello VJ,Madaio MP,Madias NE

    更新日期:1987-01-01 00:00:00

  • A bioequivalence study of oral controlled-release morphine using naltrexone blockade.

    abstract::Twenty-three normal volunteers who received morphine sulphate (MS Contin) with naltrexone completed this randomized, analytically blinded, two-way crossover comparison of the bioavailability of one 200-mg oral controlled-release morphine sulfate tablet with two 100-mg MSC tablets. Morphine effects were blocked by thre...

    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.1552-4604.1995.tb04094.x

    authors: Kaiko RF,Grandy RP,Reder RF,Goldenheim PD,Sackler RS

    更新日期:1995-05-01 00:00:00

  • Inaccuracy of hourly sampled pH measurements in describing the effect of antisecretory drugs on circadian gastric acidity.

    abstract::This study was carried out in order to verify whether gastric pH measurements obtained with continuous monitoring are more accurate in assessing the pharmacodynamic properties of antisecretory drugs than those obtained with the traditional hourly nasogastric aspiration method. Accordingly, we compared the most commonl...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1990.tb03437.x

    authors: Mela GS,Savarino V

    更新日期:1990-01-01 00:00:00

  • Effect of Intravenous Oxycodone Versus Sufentanil on the Incidence of Postoperative Nausea and Vomiting in Patients Undergoing Gynecological Laparoscopic Surgery.

    abstract::More than 30% of patients who undergo surgery will experience postoperative nausea and vomiting (PONV) if no prophylactic treatments are used. Although numerous studies have been performed to investigate the factors related to PONV, the effect of perioperative intravenous oxycodone on the incidence of PONV has not bee...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,随机对照试验

    doi:10.1002/jcph.1408

    authors: Tao B,Liu K,Wang D,Ding M,Zhao P

    更新日期:2019-08-01 00:00:00

  • Flow cytometric assessment of effects of fluvastatin on low-density lipoprotein receptor activity in stimulated T-lymphocytes from patients with heterozygous familial hypercholesterolemia.

    abstract::To test the effects of fluvastatin on low-density lipoprotein (LDL) receptor activity in patients with heterozygous familial hypercholesterolemia, the authors measured LDL receptor activity in stimulated T-lymphocytes prepared from 34 patients before and after treatment with 40 mg fluvastatin daily for 12 weeks. Maxim...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章

    doi:10.1177/00912700022009008

    authors: Raungaard B,Brorholt-Petersen JU,Jensen HK,Faergeman O

    更新日期:2000-04-01 00:00:00

  • The Clinical Pharmacology Consultation Service: results of a physician survey before and after implementation.

    abstract::A total of 175 physicians were surveyed by questionnaire before a Clinical Pharmacology Consult Service was started. Of those that responded, 72% thought the service would be helpful, although 40% said they would use the service no more than once a month. Most physicians (75%) preferred self-initiated consultations to...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1988.tb03096.x

    authors: Casner PR,Dillon KR

    更新日期:1988-01-01 00:00:00

  • Labetalol in hypertension during the third trimester of pregnancy: its antihypertensive effect and pharmacokinetic-dynamic analysis.

    abstract::The hypotensive effect, kinetics, and concentration-response relationship of labetalol, alpha beta- and alpha 1-adrenoceptor blocking drug, were studied in seven women with a moderate-to-severe hypertension (averaged diastolic blood pressure [DBP] of 100 to 120 mm Hg measured during a 1- to 2-day hospitalization perio...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1993.tb01933.x

    authors: Saotome T,Minoura S,Terashi K,Sato T,Echizen H,Ishizaki T

    更新日期:1993-10-01 00:00:00

  • Tolerance of healthy adult males in intravenous infusion of cetiedil, a vasoerythroactive drug.

    abstract::The intravenous infusion of cetiedil to a group of ten male volunteers elicited atropine-like side effects on salivation, bronchomotor tone and visual accommodation. With repeated infusions of cetiedil, the incidence as well as the duration of the side effects were reduced significantly, indicating the development of ...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1982.tb02668.x

    authors: Lewis GP,Cho YW

    更新日期:1982-05-01 00:00:00

  • Off-Label Treatment of 4 Amyotrophic Lateral Sclerosis Patients With 4-Aminopyridine.

    abstract::Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by degeneration of the upper and lower motor neuron. Among the at least 25 known genes associated with familial (hereditary) and sporadic ALS, mutations in fused-in-sarcoma (FUS) and superoxide dismutase 1 (SOD1) have been extensively investigated i...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/jcph.1437

    authors: Peikert K,Naumann M,Günther R,Wegner F,Hermann A

    更新日期:2019-10-01 00:00:00

  • Pregnancy-induced changes in the long-term pharmacokinetics of 1.1 mg vs. 5 mg folic acid: a randomized clinical trial.

    abstract::The objective of this randomized clinical trial was to compare steady-state gestational RBC and plasma folate concentrations in pregnant women supplementing daily with 1.1 mg (regular dose) vs. 5 mg (high dose) folic acid. Thirty-seven pregnant women, who were not previously taking folic acid, were enrolled in this op...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,随机对照试验

    doi:10.1002/jcph.387

    authors: Shere M,Nguyen P,Tam C,Stern S,Kapur B,O'Connor DL,Koren G

    更新日期:2015-02-01 00:00:00

  • Pharmacokinetics and tolerability of intravenous trecovirsen (GEM 91), an antisense phosphorothioate oligonucleotide, in HIV-positive subjects.

    abstract::Trecovirsen, a 25-mer antisense phosphorothioate oligonucleotide targeted at the gag site of the HIV gene, was administered to HIV-positive volunteers as an i.v. infusion. Single doses ranged from 0.1 to 2.5 mg/kg in an ascending escalation in cohorts of 6 to 12 subjects. Plasma trecovirsen concentrations and pharmaco...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章

    doi:10.1177/00912709922007552

    authors: Séréni D,Tubiana R,Lascoux C,Katlama C,Taulera O,Bourque A,Cohen A,Dvorchik B,Martin RR,Tournerie C,Gouyette A,Schechter PJ

    更新日期:1999-01-01 00:00:00

  • Pharmacokinetics of retinoids in women after meal consumption or vitamin A supplementation.

    abstract::These studies were conducted to evaluate the pharmacokinetics of several retinoids after meal consumption or vitamin A supplementation to establish a reference for future assessment of teratogenic risks of retinoid therapeutic agents. In the first study, 36 healthy young female volunteers consumed single meals contain...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1996.tb04253.x

    authors: Chen C,Mistry G,Jensen B,Heizmann P,Timm U,van Brummelen P,Rakhit AK

    更新日期:1996-09-01 00:00:00

  • An apomorphine-induced vomiting model for antiemetic studies in man.

    abstract::Apomorphine-induced vomiting is often used for preclinical efficacy testing of putative antiemetics in normal volunteers. The usual technique of individual intravenous titration for finding the threshold emitic dose of apomorphine in each subject is slow and tedious. We used a uniform dose of 0.05 mg/kg apomorphine gi...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1978.tb02427.x

    authors: Proctor JD,Chremos AN,Evans EF,Wasserman AJ

    更新日期:1978-02-01 00:00:00