Abstract:
PURPOSE:To apply physiologically-based pharmacokinetic (PBPK) modeling to investigate the consequences of reduction in activity of hepatic and intestinal uptake and efflux transporters by cyclosporine and its metabolite AM1. METHODS:Inhibitory potencies of cyclosporine and AM1 against OATP1B1, OATP1B3 and OATP2B1 were investigated in HEK293 cells +/- pre-incubation. Cyclosporine PBPK model implemented in Matlab was used to assess interaction potential (+/- metabolite) against different processes (uptake, efflux and metabolism) in liver and intestine and to predict quantitatively drug-drug interaction with repaglinide. RESULTS:Cyclosporine and AM1 were potent inhibitors of OATP1B1 and OATP1B3, IC(50) ranging from 0.019-0.093 μM following pre-incubation. Cyclosporine PBPK model predicted the highest interaction potential against liver uptake transporters, with a maximal reduction of >70% in OATP1B1 activity; the effect on hepatic efflux and metabolism was minimal. In contrast, 80-97% of intestinal P-gp and CYP3A4 activity was reduced due to the 50-fold higher cyclosporine enterocytic concentrations relative to unbound hepatic inlet. The inclusion of AM1 resulted in a minor increase in the predicted maximal reduction of OATP1B1/1B3 activity. Good predictability of cyclosporine-repaglinide DDI and the impact of dose staggering are illustrated. CONCLUSIONS:This study highlights the application of PBPK modeling for quantitative prediction of transporter-mediated DDIs with concomitant consideration of P450 inhibition.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Gertz M,Cartwright CM,Hobbs MJ,Kenworthy KE,Rowland M,Houston JB,Galetin Adoi
10.1007/s11095-012-0918-ysubject
Has Abstractpub_date
2013-03-01 00:00:00pages
761-80issue
3eissn
0724-8741issn
1573-904Xjournal_volume
30pub_type
杂志文章abstract::The present review discusses drugs and counter ions suitable for ion pair transport (IPT). Ion pairing is shown to effectively increase the lipophilicity and transport rate of polar drugs across lipid membranes. The proposed mechanisms of IPT are discussed in detail. A marked change in drug properties upon ion pair fo...
journal_title:Pharmaceutical research
pub_type: 杂志文章,评审
doi:10.1023/a:1015963128124
更新日期:1989-09-01 00:00:00
abstract::The intrasubject and intersubject variabilities for CGS 16617, an angiotensin converting enzyme inhibitor, were evaluated in an open-label, repeat single-dose bioavailability trial. Eight healthy male volunteers each received a 20-mg oral dose of CGS 16617 as an aqueous solution on four separate occasions. Components ...
journal_title:Pharmaceutical research
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doi:10.1023/a:1015954609527
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abstract:PURPOSE:To provide a systematic biophysical approach towards a better understanding of impact of conjugation chemistry on higher order structure and physical stability of an antibody drug conjugate (ADC). METHODS:ADC was prepared using thiol-maleimide chemistry. Physical stabilities of ADC and its parent IgG1 mAb were...
journal_title:Pharmaceutical research
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-007-9331-3
更新日期:2008-04-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/B:PHAM.0000019293.57927.7f
更新日期:2004-03-01 00:00:00
abstract::The effect of different concentrations of polyvinyl alcohol 14000 and 72000 (PVA 14 and 72) on the activity of betamethasone and phenylephrine hydrochloride in the rabbit eye was investigated. The polymer of higher molecular weight exerts a more pronounced effect at relatively lower viscosities. Effects on the intraoc...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/A:1016398915965
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abstract:PURPOSE:Carboxylesterases are important in the detoxification of drugs, pesticides and other xenobiotics. This study was to evaluate a series of substrates and inhibitors for characterizing these enzymes. METHODS:A series of novel aliphatic esters and thioesters were used in spectral assays to monitor human, murine an...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1016071311190
更新日期:1996-10-01 00:00:00
abstract:PURPOSE:Models to predict membrane-water partition coefficients (Kp) as a function of drug structure, membrane composition, and solution properties would be useful. This study explores the partitioning of dexamethasone (Dex) and its ionizable 21-phosphate (Dex-P) in liposomes varying in acyl chain length, physical stat...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-013-1143-z
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abstract::The internalization of a neuromodulatory adrenocorticotropic hormone (ACTH) analogue, [125I]ebiratide (H-Met(O2)-Glu[125I]His-Phe-D-Lys-Phe-NH(CH2)2NH2), was examined in cultured monolayers of bovine brain capillary endothelial cells (BCEC). HPLC analysis of the incubation solution showed that [125I]ebiratide was not ...
journal_title:Pharmaceutical research
pub_type: 杂志文章
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更新日期:1992-04-01 00:00:00
abstract::A novel floating controlled-release drug delivery system was formulated in an effort increase the gastric retention time of the dosage form and to control drug release. The buoyancy was attributed to air and oil entrapped in the agar gel network. A floating controlled-release 300-mg theophylline tablet having a densit...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1018921830385
更新日期:1993-09-01 00:00:00
abstract::An alternative procedure for the simultaneous determination of trimethoprim and sulfamethoxazole in an intravenous pharmaceutical formulation is presented. Infrared spectra of 14 calibration and 6 validation samples were collected using Fourier transform-infrared/attenuated total reflectance (FT-IR/ATR). Partial least...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1015957632242
更新日期:1989-07-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1016484522113
更新日期:1996-11-01 00:00:00
abstract:PURPOSE:Labrasol and Gelucire 44/14 are defined admixtures of acylglycerols and PEG esters which are substrates for digestive lipases. METHODS:We investigated their in vitro gastrointestinal lipolysis to understand which compounds are, after digestion, responsible for keeping poorly water-soluble drugs in solution. Th...
journal_title:Pharmaceutical research
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更新日期:2009-08-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1018974131236
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abstract:PURPOSE:To study the physical and release properties of different molecular weight (MW) pH- and temperature-responsive statistical terpolymers and beads of N-isopropylacrylamide (NIPAAm), butylmethacrylate (BMA) and acrylic acid (AA). METHODS:Random terpolymers of varying MW were synthesized with NIPAAm/BMA/AA of feed...
journal_title:Pharmaceutical research
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abstract:PURPOSE:The aim of the study was to evaluate organogel nanoparticles as a lipophilic vehicle to increase the oral bioavailability of poorly soluble compounds. Efavirenz (EFV), a Biopharmaceutical Classification System (BCS) Class II, was used as drug model. METHODS:Organogel nanoparticles loaded with EFV were formulat...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-020-02808-w
更新日期:2020-05-11 00:00:00
abstract::The effects of skin storage, skin preparation, skin pretreatment with a penetration enhancer, and skin barrier removal by adhesive tape-stripping on the concurrent cutaneous transport and metabolism of nitroglycerin (GTN) have been studied in vitro using hairless mouse skin. Storing the skin for 10 days at 4 degrees C...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1015822431178
更新日期:1992-03-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1018875130152
更新日期:1999-04-01 00:00:00
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journal_title:Pharmaceutical research
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更新日期:1992-12-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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更新日期:2019-02-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1018945401484
更新日期:1994-11-01 00:00:00
abstract:PURPOSE:Modulating sialylation of therapeutic glycoproteins may be used to influence their clearance and systemic exposure. We studied the effect of low and high sialylated IL4-10 fusion protein (IL4-10 FP) on in vitro and in vivo bioactivity and evaluated the effect of differential sialylation on pharmacokinetic param...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-019-2744-y
更新日期:2019-12-26 00:00:00
abstract::Emulsions (o/w) were prepared from solid-state emulsions comprised of various matrix materials and oils and the resultant particle size properties determined. Results suggest that for those matrices that can form solid-state emulsions, the droplet size decreased as a function of time, as previously observed. The final...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1018912100826
更新日期:1993-08-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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更新日期:2006-09-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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更新日期:1993-02-01 00:00:00
abstract::The influence of varying protein and fat content in milk of New Zealand White rabbits on the milk-to-plasma drug concentration (M/P) ratio of diazepam was studied. At various time points after littering, a bolus dose (1.5 mg/kg) followed by a 26-hr infusion (1.8 mg/h) of diazepam was administered to freely moving rabb...
journal_title:Pharmaceutical research
pub_type: 杂志文章
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更新日期:1992-10-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1021457911533
更新日期:2002-12-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1011071401306
更新日期:2001-03-01 00:00:00