Abstract:
:An analysis of pH-induced changes of drug binding may contribute to the understanding of the mechanisms involved and the clinical relevance. A literature search was performed, and acceptance criteria set up, to select reported data for quantitative evaluation. The relationship between percentage of unbound drug, fu, and pH was analyzed, and the relevance of physicochemical characteristics of the ligand drugs and the importance of hydrogen ion-induced changes in plasma proteins for the pH sensitivity of the binding were evaluated. With all basic and the majority of acidic drugs, fu depended linearly on pH. Basic drugs showed a consistent behavior with fu decreasing with increasing pH. Acidic compounds behaved differently: With some, fu increased, and with others fu decreased, with pH, and with a third group of acids fu was pH independent. Large differences in the pH sensitivity of the plasma protein binding among individual compounds were found. The fu in plasma for some bases and acids increased up to 136% and 95%, respectively, at pH values seen in severe acidemia or alkemia. These changes in fu could be clinically relevant with narrow-therapeutic-range drugs. Physicochemical properties and other characteristics of the ligands affect the pH sensitivity of the interaction with plasma proteins, but there was clear evidence indicating that pH-induced changes in the plasma proteins are also involved in the observed pH-dependent interaction with ligands. It is generally accepted that the unbound, free fraction in whole blood or plasma is an important determinant of the pharmacokinetics and pharmacodynamics of drugs. pH-dependent protein binding and consequent changes in the free fraction have been reported for many drugs. From a basic science point of view, the systematic study of pH-induced perturbations of the drug-protein interaction may provide insight into the mechanism and forces involved in the binding of drugs to plasma proteins. From a clinical viewpoint it may be of interest to know the extent of pH-induced changes in the unbound fraction of drugs under extreme acidemic or alkalemic conditions. Arterial blood pH values compatible with life reportedly range between 6.7 and 8.0. pH values as low as 6.3 have been measured in survivors of drowning accidents. To the best knowledge of the authors, a review and interpretation of pH-associated changes in the protein binding of drugs has not been attempted to date. The goals of this investigation were to (1) review published results of studies that determined the impact of pH changes on the protein binding of drugs in man, (2) select representative data using predetermined criteria, (3) determine relevant factors impacting the pH sensitivity of the drug-protein interaction, and (4) attempt to interpret the results and their clinical relevance.
journal_name
Ther Drug Monitjournal_title
Therapeutic drug monitoringauthors
Hinderling PH,Hartmann Ddoi
10.1097/00007691-200502000-00014subject
Has Abstractpub_date
2005-02-01 00:00:00pages
71-85issue
1eissn
0163-4356issn
1536-3694pii
00007691-200502000-00014journal_volume
27pub_type
杂志文章abstract::Several lipophilic, cytotoxic drugs, or both, (including anticancer drugs [Vinca alkaloids, doxorubicin, cyclosporin A, and digoxin]) have proven to be actively effluxed by P-glycoprotein (P-gp) expressed at the luminal membrane of the brain capillary endothelial cells, resulting in the very low apparent blood-brain b...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章,评审
doi:10.1097/00007691-199810000-00024
更新日期:1998-10-01 00:00:00
abstract::The adsorption of amitriptyline, desipramine, doxepin, imipramine, and nortriptyline onto cholestyramine was demonstrated in vitro with use of 1.2 mol/L HCl at 37 degrees C to simulate gastric fluid. Binding to cholestyramine was approximately 80% for each of the tricyclic antidepressants, and this was about the same ...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/00007691-199208000-00014
更新日期:1992-08-01 00:00:00
abstract:BACKGROUND:Hydroxychloroquine (HCQ) is an effective treatment for patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) and has been used for these patients in more than 70 nations. However, in Japan, HCQ has not been approved for CLE or SLE. To establish an appropriate therapeutic reg...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/FTD.0000000000000261
更新日期:2016-04-01 00:00:00
abstract::Mixed-effect modeling has been suggested as a possible tool to detect and describe drug interactions in patient populations receiving drug combinations for the treatment of disease states. The mixed-effect modeling program, NONMEM, was used to measure the effects of the well-known digoxin-quinidine and digoxin-verapam...
journal_title:Therapeutic drug monitoring
pub_type: 临床试验,杂志文章
doi:10.1097/00007691-199602000-00008
更新日期:1996-02-01 00:00:00
abstract:BACKGROUND:In children with cystic fibrosis (CF), the currently recommended amikacin dose ranges between 30-35 mg/kg/day; however, data supporting this dosing efficacy is lacking. Herein, the objectives were to develop a non-parametric pharmacokinetic population model (POPPK) for amikacin in children with CF and invest...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/FTD.0000000000000855
更新日期:2020-12-17 00:00:00
abstract::5-Methoxy-N,N-dialkyltryptamines are tryptamine derivatives that possess strong hallucinogenic effects. Because of their escalating popularity and potent physiological effects, an increasing number of acute poisoning cases have been reported in various countries. For their metabolism in humans, only a few studies have...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/FTD.0b013e3181dcb40c
更新日期:2010-06-01 00:00:00
abstract::Therapeutic drug monitoring (TDM) is commonly employed to optimize the dosing of certain drugs, including digoxin, aminoglycosides, theophylline, and phenytoin. Studies were reviewed in order to (a) evaluate the effect of TDM on the occurrence of toxic drug reactions (TDRs) and (b) identify factors that may modify or ...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章,meta分析
doi:10.1097/00007691-199001000-00013
更新日期:1990-01-01 00:00:00
abstract::The emergence of point-of-care assays enabling bedside testing such as the VerifyNow P2Y12 system might prove useful in clinical settings. The aim of this study was to evaluate the ability of the VerifyNow P2Y12 assay to estimate the inhibition of platelet aggregation provided by clopidogrel in the absence of baseline...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章,随机对照试验
doi:10.1097/FTD.0b013e3181757c59
更新日期:2008-06-01 00:00:00
abstract::Measurement of whole blood and plasma levels of cyclosporin A (CsA) by radioimmunoassay in kidney transplant recipients receiving the drug showed that CsA concentrations in plasma increased nonlinearly when whole blood levels of the drug exceeded 1,000 ng/ml. At low plasma levels (less than 200 ng/ml), most of the CsA...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/00007691-198503000-00010
更新日期:1985-01-01 00:00:00
abstract::A reverse-phase high-performance liquid chromatographic (HPLC) method for the measurement of lamotrigine (LTG) simultaneously with phenobarbitone (PB), phenytoin (PHT), and carbamazepine (CBZ) is described using hexobarbital as the internal standard. The method uses the chromophore at 307 nm to detect LTG in the prese...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/00007691-199402000-00013
更新日期:1994-02-01 00:00:00
abstract::Recent literature has urged caution in the interpretation of vancomycin serum concentrations in patients with end-stage renal disease (ESRD), because falsely elevated levels in excess of 70% have been reported with the most commonly used fluorescence polarization immunoassay (FPIA). The purpose of this study was to ev...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/00007691-199804000-00016
更新日期:1998-04-01 00:00:00
abstract:BACKGROUND:A fast and easy-to-use liquid chromatography-tandem mass spectrometry method for the determination and quantification of 6 triazoles [fluconazole (FLZ), isavuconazole (ISZ), itraconazole (ITZ), hydroxy-itraconazole (OH-ITZ), posaconazole (PSZ), and voriconazole (VRZ)] in human plasma and serum was developed ...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/FTD.0000000000000438
更新日期:2017-10-01 00:00:00
abstract::A population analysis of the kinetics of lithium was performed from experimental and observational data in 113 subjects in order to propose a new approach for lithium dosage individualization. The kinetics of lithium is described by a two-compartment model. Age, body weight, height, and serum creatinine are included a...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/00007691-199406000-00006
更新日期:1994-06-01 00:00:00
abstract:BACKGROUND:The anticonvulsant properties of phenytoin (PHT) were discovered in 1938. Since then, it has been one of the most widely used antiepileptic drugs. It is slowly absorbed, extensively plasma protein-bound, exhibits a nonlinear, concentration-dependent pharmacokinetic profile, and has a narrow therapeutic range...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/FTD.0b013e3182081089
更新日期:2011-02-01 00:00:00
abstract::Despite its known teratogenic effects, thalidomide has been used to treat a variety of diseases ranging from alleviation of autoimmune disorders to prevention of metastasis of cancers. The exact method of action of thalidomide and its derivatives is still under investigation. Thalidomide undergoes very little metaboli...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/00007691-200202000-00017
更新日期:2002-02-01 00:00:00
abstract::Hair testing procedures allow a cumulative reflection of long-term drug abuse and are useful as a test for compliance in clinical toxicology. In the present study, liquid chromatography coupled with tandem mass spectrometry was used to determine analgesic opioid drugs in hair samples. The procedure used a simple metha...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/FTD.0b013e318155a329
更新日期:2007-10-01 00:00:00
abstract::Sotrastaurin (AEB071) is an investigational immunosuppressant that blocks T-lymphocyte activation through protein kinase C inhibition. It is currently in Phase II of clinical development for the prevention of acute rejection after solid organ transplantation. In renal transplant clinical trials, sotrastaurin has been ...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章,评审
doi:10.1097/FTD.0b013e3181ee9e26
更新日期:2010-10-01 00:00:00
abstract::The analysis of pemoline (2-imino-5-phenyl-4-oxazolidine) by a rapid, sensitive, and specific high performance liquid chromatographic assay using ultraviolet detection is described. Only 100 microliters of plasma or serum is required. Analytical recoveries of 88% for pemoline and 93% for the internal standard (4-methy...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/00007691-198007000-00009
更新日期:1980-01-01 00:00:00
abstract::A variety of medications are used in treating patients infected with the human immunodeficiency virus (HIV). These medications are used to control viremia and to prevent and treat opportunistic infections. An individual is often required to take numerous drugs at the same time and thus clinicians are confronted with p...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章,评审
doi:10.1097/00007691-200112000-00001
更新日期:2001-12-01 00:00:00
abstract:BACKGROUND:Valproic acid (VPA) is frequently used together with clozapine (CLZ) as mood-stabilizer or for the prevention of seizures in patients with psychotic disorders. VPA is known to reduce levels of the pharmacologically active CLZ-metabolite N-desmethylclozapine (N-DMC), but factors determining the degree of this...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/FTD.0000000000000619
更新日期:2019-08-01 00:00:00
abstract:BACKGROUND:Analysis of residual gene expression of the nuclear factor of activated T cell (NFAT)-regulated genes has been developed as a pharmacodynamic biomarker to monitor therapy with calcineurin inhibitors. The availability of commercial primer sets (Search-LC) and the well-established assay protocol makes this bio...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/FTD.0000000000000340
更新日期:2016-12-01 00:00:00
abstract:BACKGROUND:Several reports of loss of efficacy or adverse effects have been described after generic substitution of antipsychotics. To date, studies comparing serum drug levels in patients switched to generic antipsychotics in a standard clinical setting are lacking. The aim of this study was to investigate if switchin...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/FTD.0000000000000211
更新日期:2015-12-01 00:00:00
abstract:BACKGROUND:In humans, donepezil (D) is metabolized to 5-O-desmethyl-donepezil (5DD), 6-O-desmethyl-donepezil (6DD), and donepezil-N-oxide (DNox). Although 6DD and DNox are pharmacologically active, the activity of 5DD is unknown. At present, no routine methods are available to detect D and its 3 metabolites simultaneou...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/FTD.0000000000000246
更新日期:2016-02-01 00:00:00
abstract::Our aim was to evaluate the isolated placental lobule to study maternofetal transplacental digoxin transfer and accumulation in placental tissue in vitro. Digoxin passage across the isolated lobule of 10 human placentas was calculated from repeated fetal and maternal perfusate samples, and placental tissue digoxin con...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/00007691-199702000-00002
更新日期:1997-02-01 00:00:00
abstract::The pharmacokinetic interaction between chloroquine (CQ) and imipramine was investigated in six healthy volunteers who received 300 mg of CQ, 50 mg of imipramine, and combined doses of both drugs in a randomized, crossover design. Blood and urine samples were collected at predetermined time intervals and were analyzed...
journal_title:Therapeutic drug monitoring
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1097/00007691-199302000-00008
更新日期:1993-02-01 00:00:00
abstract:BACKGROUND:The indication for the antiepileptic drug lacosamide (LCM) was recently extended to include children from the age of 4 years. Real-life data on the use and serum concentrations of LCM in children and adolescents are limited. The purpose of this study was to investigate the use of LCM in this patient group in...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/FTD.0000000000000599
更新日期:2019-06-01 00:00:00
abstract:BACKGROUND:Anti-T lymphocyte globulin (ATLG) modulates the alloreactivity of T lymphocytes, reducing the risk of immunological posttransplant complications, in particular rejection and graft-versus-host disease, after allogeneic hematopoietic stem cell transplantation (HSCT). We developed and validated a new enzyme-lin...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/FTD.0000000000000407
更新日期:2017-06-01 00:00:00
abstract::Individualized tobramycin therapy was systemically evaluated in 26 patients with gram-negative pneumonias involving Pseudomonas aeruginosa and other multiple antibiotic-resistant pathogens. Patient prognoses were classified by underlying diseases, and response was determined according to previously established criteri...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:
更新日期:1980-01-01 00:00:00
abstract::Monitoring of serum voriconazole concentrations has been proposed to optimize therapeutic effect and minimize toxicity. However, little is known about the clinical use of voriconazole therapeutic drug monitoring (TDM) by treating physicians. Four hundred seventy-eight episodes corresponding with 161 adult patients (me...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/FTD.0b013e3181ea3de6
更新日期:2010-10-01 00:00:00
abstract:BACKGROUND:Stiripentol (STP) was approved as an orphan drug in 2007 in Europe as adjunctive therapy with valproic acid (VPA) and clobazam (CLB) for Dravet syndrome. Dravet syndrome is a highly pharmacoresistant form of epilepsy, which starts in early childhood. Data about STP pharmacokinetics and interactions are still...
journal_title:Therapeutic drug monitoring
pub_type: 杂志文章
doi:10.1097/FTD.0b013e31825dc4a6
更新日期:2012-08-01 00:00:00