Pharmacokinetics of the oral direct renin inhibitor aliskiren in combination with digoxin, atorvastatin, and ketoconazole in healthy subjects: the role of P-glycoprotein in the disposition of aliskiren.

Abstract:

:This study investigated the potential pharmacokinetic interaction between the direct renin inhibitor aliskiren and modulators of P-glycoprotein and cytochrome P450 3A4 (CYP3A4). Aliskiren stimulated in vitro P-glycoprotein ATPase activity in recombinant baculovirus-infected Sf9 cells with high affinity (K(m) 2.1 micromol/L) and was transported by organic anion-transporting peptide OATP2B1-expressing HEK293 cells with moderate affinity (K(m) 72 micromol/L). Three open-label, multiple-dose studies in healthy subjects investigated the pharmacokinetic interactions between aliskiren 300 mg and digoxin 0.25 mg (n = 22), atorvastatin 80 mg (n = 21), or ketoconazole 200 mg bid (n = 21). Coadministration with aliskiren resulted in changes of <30% in AUC(tau) and C(max,ss) of digoxin, atorvastatin, o-hydroxy-atorvastatin, and rho-hydroxy-atorvastatin, indicating no clinically significant interaction with P-glycoprotein or CYP3A4 substrates. Aliskiren AUC(tau) was significantly increased by coadministration with atorvastatin (by 47%, P < .001) or ketoconazole (by 76%, P < .001) through mechanisms most likely involving transporters such as P-glycoprotein and organic anion-transporting peptide and possibly through metabolic pathways such as CYP3A4 in the gut wall. These results indicate that aliskiren is a substrate for but not an inhibitor of P-glycoprotein. On the basis of the small changes in exposure to digoxin and atorvastatin and the <2-fold increase in exposure to aliskiren during coadministration with atorvastatin and ketoconazole, the authors conclude that the potential for clinically relevant drug interactions between aliskiren and these substrates and/or inhibitors of P-glycoprotein/CPY3A4/OATP is low.

journal_name

J Clin Pharmacol

authors

Vaidyanathan S,Camenisch G,Schuetz H,Reynolds C,Yeh CM,Bizot MN,Dieterich HA,Howard D,Dole WP

doi

10.1177/0091270008323258

subject

Has Abstract

pub_date

2008-11-01 00:00:00

pages

1323-38

issue

11

eissn

0091-2700

issn

1552-4604

pii

0091270008323258

journal_volume

48

pub_type

临床试验,杂志文章
  • Effects of hetastarch and albumin on coagulation in patients with septic shock.

    abstract::The effect of 6% hydroxyethyl starch (hetastarch) and 5% human serum albumin (albumin) infusion on coagulation in 12 patients with septic shock was evaluated. Patients were randomly assigned to receive either albumin (N = 6) or hetastarch (N = 6) infusion over a 24-hour study interval. The prothrombin time (PT), parti...

    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.1552-4604.1988.tb05751.x

    authors: Falk JL,Rackow EC,Astiz ME,Weil MH

    更新日期:1988-05-01 00:00:00

  • Calcium channel blockade in experimental aminoglycoside nephrotoxicity.

    abstract::Calcium channel blocker therapy has proved protective in certain models of ischemic-induced acute renal failure. This effect may be related to the prevention of calcium influx into injured cells or by the vasodilatory effects of verapamil that may result in an improvement in renal blood flow. In the current study, the...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1987.tb03076.x

    authors: Watson AJ,Gimenez LF,Klassen DK,Stout RL,Whelton A

    更新日期:1987-08-01 00:00:00

  • Single-dose pharmacokinetics of repaglinide in subjects with chronic liver disease.

    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

    authors: Hatorp V,Walther KH,Christensen MS,Haug-Pihale G

    更新日期:2000-02-01 00:00:00

  • Intravitreal Injection of a Rho-Kinase Inhibitor (Fasudil) for Recent-Onset Nonarteritic Anterior Ischemic Optic Neuropathy.

    abstract::This study evaluated the effects of intravitreal injection of fasudil (IVF), a Rho-kinase inhibitor, in cases of recent-onset nonarteritic anterior ischemic optic neuropathy (NAION). In this interventional case series, 13 eyes of 13 patients diagnosed with NAION within 14 days of onset were included. The affected eyes...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/jcph.655

    authors: Sanjari N,Pakravan M,Nourinia R,Esfandiari H,Hafezi-Moghadam A,Zandi S,Nakao S,Shah-Heidari MH,Jamali A,Yaseri M,Ahmadieh H

    更新日期:2016-06-01 00:00:00

  • Interaction between propranolol and propafenone in healthy volunteers.

    abstract::The effects of propafenone on the pharmacokinetics and pharmacodynamics of propranolol were evaluated in 12 healthy male subjects. Both propafenone and propranolol were each administered alone for one week followed by concomitant administration for an additional week. Blood samples, obtained at steady-state, were anal...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1989.tb03373.x

    authors: Kowey PR,Kirsten EB,Fu CH,Mason WD

    更新日期:1989-06-01 00:00:00

  • Determination of cefalexin pharmacokinetics and dosage adjustments in relation to renal function.

    abstract::Following oral administration of a single 500-mg dose of cefalexin, serum and urine levels of the antibiotic were determined comparatively in ten normal subjects, ten patients with renal impairment, and ten patients with chronic nephritis on maintenance hemodialysis. In normal subjects, mean serum peak levels (12.0 +/...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1975.tb05918.x

    authors: Brogard JM,Pinget M,Dorner M,Lavillaureix J

    更新日期:1975-10-01 00:00:00

  • Increased risk of myocardial infarction associated with angiotensin-converting enzyme gene polymorphism is age dependent.

    abstract::The angiotensin-converting enzyme (ACE) gene is a candidate genetic locus for coronary artery disease (CAD). Studies investigating the relationship between the ACE-insertion/deletion (I/D) gene polymorphism and myocardial infarction (MI) have been inconsistent. The authors hypothesized that age may be an important mod...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1177/0091270010382420

    authors: Hamelin BA,Zakrzewski-Jakubiak M,Robitaille NM,Bogaty P,Labbé L,Turgeon J

    更新日期:2011-09-01 00:00:00

  • Which studies of therapy merit credence? Vitamin E and estrogen therapy as cautionary examples.

    abstract::A vast and continuously growing amount of material on drugs exists in the literature to read and evaluate. Frequently, the papers and their recommendations are conflicting and contradictory. Readers are faced with the dilemma of deciding what to believe. The need for evidence-based medicine as a foundation for optimal...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,评审

    doi:

    authors: Spector R,Vesell ES

    更新日期:2002-09-01 00:00:00

  • Antiretrovirals for Prophylaxis Against COVID-19: A Comprehensive Literature Review.

    abstract::Although people living with human immunodeficiency virus and other comorbidities are expected to experience more grievous consequences with corona virus disease 2019 (COVID-19), recent cohort studies did not indicate this. Antiretrovirals (ARVs) might have a prophylactic role in these patients. The purpose of this stu...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/jcph.1788

    authors: Alavian G,Kolahdouzan K,Mortezazadeh M,Torabi ZS

    更新日期:2020-11-20 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

  • Improving the diagnosis of hypersensitivity reactions associated with sulfonamides.

    abstract::The differential diagnosis of idiosyncratic adverse drug reactions (ADRs) is difficult because symptoms are seldom pathognomonic. The authors compared the performance of two new diagnostic aids in the differential diagnosis of 27 cases of skin reactions associated with sulfonamide therapy. One test, the Bayesian Adver...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1994.tb04736.x

    authors: Lanctôt KL,Ghajar BM,Shear NH,Naranjo CA

    更新日期:1994-12-01 00:00:00

  • Tafenoquine at therapeutic concentrations does not prolong Fridericia-corrected QT interval in healthy subjects.

    abstract::Tafenoquine is being developed for relapse prevention in Plasmodium vivax malaria. This Phase I, single-blind, randomized, placebo- and active-controlled parallel group study investigated whether tafenoquine at supratherapeutic and therapeutic concentrations prolonged cardiac repolarization in healthy volunteers. Subj...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,随机对照试验

    doi:10.1002/jcph.302

    authors: Green JA,Patel AK,Patel BR,Hussaini A,Harrell EJ,McDonald MJ,Carter N,Mohamed K,Duparc S,Miller AK

    更新日期:2014-09-01 00:00:00

  • Single plasma concentrations of 1'-hydroxymidazolam or the ratio of 1'-hydroxymidazolam:midazolam do not predict midazolam clearance in healthy subjects.

    abstract::The 30-minute ratio of 1'-hydroxymidazolam:midazolam plasma concentrations has been used as a measure of midazolam clearance in liver transplant patients. This study determined if a single concentration of 1'-hydroxymidazolam or the ratio of 1'-hydroxymidazolam:midazolam could be used to predict midazolam clearance in...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1177/009127002401382614

    authors: Rogers JF,Nafziger AN,Kashuba AD,Streetman DS,Rocci ML Jr,Choo EF,Wilkinson GR,Bertino JS Jr

    更新日期:2002-10-01 00:00:00

  • Pharmacokinetics and antihypertensive effects of low dose clonidine during chronic therapy.

    abstract::Using a sensitive and specific radioimmunoassay the pharmacokinetic disposition of clonidine was determined in hypertensive patients after a single dose and then after 5, 28 and 56 days of chronic dosing with 75 micrograms bd. Following a single dose of clonidine maximal plasma concentrations of 0.34 +/- 0.06 ng/ml we...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1989.tb03335.x

    authors: Anavekar SN,Howes LG,Jarrott B,Syrjanen M,Conway EL,Louis WJ

    更新日期:1989-04-01 00:00:00

  • Drug effects on orthostatic intolerance induced by bedrest.

    abstract::Effective and practical preventive procedures for postflight orthostatic intolerance are highly desirable. The current practice of attempts to expand plasma volume by ingestion of salt and fluids before reentry has proven benefits. This study evaluated alternative options using fludrocortisone (F) to expand plasma vol...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1991.tb03659.x

    authors: Vernikos J,Dallman MF,Van Loon G,Keil LC

    更新日期:1991-10-01 00:00:00

  • A Retrospective Review of the Efficiency of First-Dose Therapeutic Drug Monitoring of Gentamicin, Amikacin, and Vancomycin in the Pediatric Population.

    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

    authors: Lim WXS,Chua WBB,Chua JM,Lee Q,Chan JW,Sultana R,Poh BH

    更新日期:2020-01-01 00:00:00

  • Clinical pharmacokinetics, platelet response, and safety of eltrombopag at supratherapeutic doses of up to 200 mg once daily in healthy volunteers.

    abstract::This was a double-blind, placebo-controlled, randomized, parallel, dose-escalation study to assess the pharmacokinetics, platelet response, safety, and tolerability of supratherapeutic doses of eltrombopag (100 mg, 150 mg, and 200 mg once daily) administered for 5 days to 33 healthy adult volunteers. Plasma eltrombopa...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,多中心研究,随机对照试验

    doi:10.1177/0091270010368677

    authors: Matthys G,Park JW,McGuire S,Wire MB,Bowen C,Williams D,Jenkins J,Peng B

    更新日期:2011-03-01 00:00:00

  • Absence of effect of telbivudine on cardiac repolarization: results of a thorough QT/QTc study in healthy participants.

    abstract::The effect of telbivudine on cardiac repolarization was evaluated in healthy participants at clinical and supratherapeutic doses. Sixty-two participants were enrolled, stratified by sex, and randomized according to a crossover design among 4 treatment sequences: placebo, a single moxifloxacin 400-mg dose as positive c...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章,随机对照试验

    doi:10.1177/0091270009337943

    authors: Poordad F,Zeldin G,Harris SI,Ke J,Xu L,Mayers D,Zhou XJ

    更新日期:2009-12-01 00:00:00

  • Tissue penetration of cefpodoxime and cefixime in healthy subjects.

    abstract::Microdialysis is a technique that allows the measurement of free antibiotic concentrations in different tissues, which are responsible for the antibacterial activity at the infection site. In an open, randomized, 2-way crossover study in healthy volunteers, the muscle penetration of orally administered cefpodoxime (40...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1177/0091270004273679

    authors: Liu P,Müller M,Grant M,Obermann B,Derendorf H

    更新日期:2005-05-01 00:00:00

  • Pharmacokinetics and rectal bioavailability of hydrocortisone acetate after single and multiple administration in healthy subjects and patients.

    abstract::The pharmacokinetics and bioavailability of hydrocortisone after rectal administration of a hydrocortisone acetate foam were determined after single and multiple dosing in healthy subjects as well as in patients with inflammatory bowel disease. Endogenous hydrocortisone was suppressed by dexamethasone administration. ...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章

    doi:10.1177/00912700122010410

    authors: Tromm A,Möllmann H,Barth J,Hochhaus G,Krieg M,Bigalke C,Möllmann A,Derendorf H

    更新日期:2001-05-01 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

  • Identifying medication error chains from critical incident reports: a new analytic approach.

    abstract::Research into the distribution of medication errors usually focuses on isolated stages within the medication use process. Our study aimed to provide a novel process-oriented approach to medication incident analysis focusing on medication error chains. Our study was conducted across a 900-bed teaching hospital in Switz...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/jcph.319

    authors: Huckels-Baumgart S,Manser T

    更新日期:2014-10-01 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

  • Effect of CYP2C19 genetic polymorphism on pharmacokinetics and pharmacodynamics of a new proton pump inhibitor, ilaprazole.

    abstract::It is well known that the CYP2C19 genetic polymorphism influences the pharmacokinetics and pharmacodynamics of proton pump inhibitors (PPIs), but no report has addressed the effects on ilaprazole, a newly developed PPI. To investigate the effects of the CYP2C19 genetic polymorphism on the disposition and pharmacodynam...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1177/0091270011408611

    authors: Cho H,Choi MK,Cho DY,Yeo CW,Jeong HE,Shon JH,Lee JY,Shin JS,Cho M,Kim DY,Shin JG

    更新日期:2012-07-01 00:00:00

  • Interaction between sulindac and warfarin: different results in normal subjects and in an unusual patient with a potassium-losing renal tubular defect.

    abstract::While sulindac failed to affect significantly warfarin-induced hypoprothrombinemia in normal male volunteers, it markedly prolonged prothrombin time in a patient with a renal tubular defect who had been anticoagulated with warfarin. This difference in individual response with respect to a drug interaction illustrates ...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1979.tb01644.x

    authors: Loftin JP,Vesell ES

    更新日期:1979-11-01 00:00:00

  • Evaluation of quinapril on regional blood flow and cardiac function in patients with congestive heart failure.

    abstract::Quinapril, a nonsulfhydryl ACE inhibitor, was evaluated in ten New York Heart Association (NYHA) functional class (FC) II-III CHF patients to determine its effects on regional blood flow [effective renal plasma flow (ERPF), renal blood flow (RBF), renal vascular resistance (RVR), hepatic blood flow (HBF), hepatic vasc...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1992.tb03791.x

    authors: Munger MA,Chance M,Nair R,Prescott AW,Nara AR,Simonson MS,Green JA,Posvar EL

    更新日期:1992-01-01 00:00:00

  • The effect of lovastatin on early restenosis.

    abstract::The effect of lovastatin given before percutaneous coronary angioplasty (PTCA) on early restenosis was investigated in men with mild to moderate hypercholesterolemia. Thirty-four hypercholesterolemic patients (serum LDL cholesterol 130-200 mg/dL) undergoing their first PTCA completed a 6-month prospective, double-blin...

    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.tb05017.x

    authors: Beigel Y,Zafrir N,Teplitzky Y,Neuman Y,Gavish D,Wurzel M,Fainaru M

    更新日期:1995-06-01 00:00:00

  • Effects of thyroid status and choice of USP preparation on the pharmacokinetics of propylthiouracil in the beagle dog.

    abstract::In vitro dissolution profile testing of 12 generic 6-propyl-2-thiouracil (PTU) formulations indicated significant differences in their solubilities in water and in 0.1N hydrochloric acid. Two products, representing the extremes of solubility, were subsequently tested for bioavailability. Bioavailability data from euth...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1980.tb02530.x

    authors: Ringhand P,Maxon HR,Ritschel WA,Chen IW,Bauman DH

    更新日期:1980-02-01 00:00:00

  • Ketoprofen 75 mg qid versus acetaminophen 1000 mg qid for 3 days on swelling, pain, and other postoperative events after third-molar surgery.

    abstract::A randomized, double-blind, within-patient, crossover study was carried out after bilateral "identical" surgical procedures using local anesthesia only. A 3-day tablet regime of racemic ketoprofen 75 mg or acetaminophen 1000 mg qid (x 4) was given starting 3 hours after surgery. Ketoprofen reduced objectively measured...

    journal_title:Journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1177/0091270002250603

    authors: Bjørnsson GA,Haanaes HR,Skoglund LA

    更新日期:2003-03-01 00:00:00

  • Methemoglobin levels produced by organic nitrates in patients with coronary artery disease.

    abstract::To determine if ordinary doses of nitrates produce a significant increase in methemoglobin, methemoglobin levels were measured in 59 randomly selected patients with coronary artery disease and unstable angina pectoris who were receiving organic nitrate therapy. Patients were taking isosorbide dinitrate, 2% nitroglycer...

    journal_title:Journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1002/j.1552-4604.1984.tb01825.x

    authors: Arsura E,Lichstein E,Guadagnino V,Nicchi V,Sanders M,Hollander G,Greengart A

    更新日期:1984-04-01 00:00:00