Abstract：
:The purpose of the present study was to develop a physiologically based pharmacokinetic model for dextromethorphan (DEX) and its metabolites in extensive and poor metabolizers. The model was used to study the influence of dissolution rates on the sensitivity of maximum plasma concentration and area under the concentration-time curve for immediate release formulations. Simulation of in vitro cellular transwell permeability was used to confirm lysosomal trapping. GastroPlus™ was used to build a mechanistic absorption and physiologically based pharmacokinetic model of DEX. The model simulations were conducted with and without lysosomal trapping. The simulated results matched well with observed data only when lysosomal trapping was included. The model shows that DEX is rapidly absorbed into the enterocytes, but DEX and its metabolites only appear slowly in the portal vein and plasma, presumably due to lysosomal trapping. For this class of drug, the rate of in vitro and in vivo dissolution is not a sensitive factor in determining bioequivalence. This study shows that dissolution and the rate of absorption into the enterocytes are clinically irrelevant for the performance of DEX immediate release product. An understanding of the entire underlying mechanistic processes of drug disposition is needed to define clinically relevant product specifications for DEX.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Bolger MB,Macwan JS,Sarfraz M,Almukainzi M,Löbenberg Rdoi
10.1016/j.xphs.2018.09.036subject
Has Abstractpub_date
2019-01-01 00:00:00pages
268-278issue
1eissn
0022-3549issn
1520-6017pii
S0022-3549(18)30599-9journal_volume
108pub_type
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更新日期：1998-08-01 00:00:00
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journal_title：Journal of pharmaceutical sciences
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doi：10.1002/jps.2600700413
更新日期：1981-04-01 00:00:00
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pub_type： 临床试验,杂志文章,随机对照试验
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doi：10.1002/jps.2600680732
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journal_title：Journal of pharmaceutical sciences
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abstract：:In vitro percutaneous permeation of betamethasone 17-valerate through excised human skin was studied. Pressure-sensitive silicone adhesive containing betamethasone 17-valerate in suspension was used as a vehicle. Steady-state flux through the split-thickness skin was similar to that through the isolated epidermis. How...
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