Abstract
Physiologically based pharmacokinetic (PBPK) models for the intestine, comprising of different flow rates perfusing the enterocyte region, were revisited for appraisal of flow affects on the intestinal availability (FI) and, in turn, the systemic availability (Fsys) and intestinal versus liver contribution to the first-pass effect during oral drug absorption. The traditional model (TM), segregated flow model (SFM), and effective flow (QGut) model stipulate that 1.0, ∼0.05 to 0.3, and ≤0.484× of the total intestinal flow, respectively, reach the enterocyte region that houses metabolically active and transporter-enriched enterocytes. The fractional flow rate to the enterocyte region (fQ), when examined under varying experimental conditions, was found to range from 0.024 to 0.2 for the SFM and 0.065 to 0.43 for the QGut model. Appraisal of these flow intestinal models, when used in combination with whole-body PBPK models, showed the ranking as SFM < QGut model < TM in the description of FI, and the same ranking existed for the contribution of the intestine to first-pass removal. However, the ranking for the predicted contribution of hepatic metabolism, when present, to first-pass removal was the opposite: SFM > QGut model > TM. The findings suggest that the fQ value strongly influences the rate of intestinal metabolism (FI and Fsys) and indirectly affects the rate of liver metabolism due to substrate sparing effect. Thus, the fQ value in the intestinal flow models pose serious implications on the interpretation of data on the first-pass effect and oral absorption of drugs.
Footnotes
This work was supported by the Canadian Institute for Health Research (to K.S.P.); and the Alexander Graham Bell National Science and Engineering Research Council (NSERC) fellowship, National Science and Engineering Research Council of Canada, NSERC (to E.C.Y.C.).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
ABBREVIATIONS:
- PBPK
- physiologically based pharmacokinetic
- FI or FG
- intestinal availability
- FH
- hepatic availability
- Fsys
- systemic availability
- Fabs
- fraction absorbed
- TM
- traditional model
- SFM
- segregated flow model
- Qen
- low enterocyte flow
- fQ
- fractional flow rate to the enterocyte region
- QPV
- portal venous flow
- Qgut
- effective flow
- Qvilli
- villous flow
- P-gp
- P-glycoprotein
- po
- oral
- iv
- intravenous
- CLint,met
- metabolic intrinsic clearance
- P
- precursor drug
- CLint,met1,H
- metabolic intrinsic clearance for liver
- CLint,sec,I
- intestinal secretion clearance
- CLint,sec,H
- liver biliary intrinsic clearance
- CLd1 and CLd2
- influx and efflux intrinsic clearances
- CLint,I
- total intestinal intrinsic clearance
- CLint,H
- total liver intrinsic clearance
- fB
- unbound fraction in blood
- fI
- unbound fraction in intestine
- fH
- unbound fraction in liver
- AUC
- area under the curve
- ka
- absorption rate constant
- kg
- luminal degradation rate constant
- Papp
- apparent permeability
- CLperm
- drug permeability clearance
- Peff
- effective permeability
- vI
- rate of intestinal removal
- vH
- rate of hepatic removal
- E
- extraction ratio
- CA
- arterial concentration
- STM
- segmental traditional model
- SSFM
- segmental segregated flow model
- C̅PV
- flow-averaged portal venous concentration.
- Received March 30, 2012.
- Accepted June 27, 2012.
- Copyright © 2012 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.
|