Abstract
This study aimed to establish a practical and convenient method of predicting intestinal availability (Fg) in humans for highly permeable compounds at the drug discovery stage, with a focus on CYP3A4-mediated metabolism. We constructed a “simplified Fg model,” described using only metabolic parameters, assuming that passive diffusion is dominant when permeability is high and that the effect of transporters in epithelial cells is negligible. Five substrates for CYP3A4 (alprazolam, amlodipine, clonazepam, midazolam, and nifedipine) and four for both CYP3A4 and P-glycoprotein (P-gp) (nicardipine, quinidine, tacrolimus, and verapamil) were used as model compounds. Observed fraction of drug absorbed (FaFg) values for these compounds were calculated from in vivo pharmacokinetic (PK) parameters, whereas in vitro intestinal intrinsic clearance (CLint,intestine) was determined using human intestinal microsomes. The CLint,intestine for the model compounds corrected with that of midazolam was defined as CLm,index and incorporated into a simplified Fg model with empirical scaling factor. Regardless of whether the compound was a P-gp substrate, the FaFg could be reasonably fitted by the simplified Fg model, and the value of the empirical scaling factor was well estimated. These results suggest that the effects of P-gp on Fa and Fg are substantially minor, at least in the case of highly permeable compounds. Furthermore, liver intrinsic clearance (CLint,liver) can be used as a surrogate index of intestinal metabolism based on the relationship between CLint,liver and CLm,index. Fg can be easily predicted using a simplified Fg model with the empirical scaling factor, enabling more confident selection of drug candidates with desirable PK profiles in humans.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.029322.
-
ABBREVIATIONS:
- PK
- pharmacokinetic(s)
- Fa
- fraction of drug absorbed
- Fg
- intestinal availability
- Fh
- hepatic availability
- P-gp
- P-glycoprotein
- PSinf
- apparent influx clearance
- PSeff
- efflux clearance
- CLab
- absorption clearance
- CLm
- metabolic clearance
- Q
- luminal flow rate
- CLint,intestine
- intestinal intrinsic clearance
- CLm,index
- intestinal intrinsic clearance corrected with that of midazolam
- CLint,liver
- liver intrinsic clearance
- HIM
- human intestinal microsome
- HLM
- human liver microsome
- PAMPA
- parallel artificial membrane permeability assay
- DMSO
- dimethyl sulfoxide
- Papp
- apparent permeability coefficient
- LC/MS/MS
- liquid chromatography/tandem mass spectrometry
- P450
- cytochrome P450
- CLh
- hepatic clearance
- CLtot
- total body clearance
- CLr
- renal clearance
- Qh
- hepatic blood flow
- Rb
- blood-to-plasma concentration ratio
- SF
- scaling factor
- α
- empirical scaling factor.
- Received July 14, 2009.
- Accepted March 30, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|