Abstract
Recently, a physiologically-based, segregated flow model that incorporates separate intestinal tissue and flow to both a nonabsorptive and an absorptive outermost layer (enterocytes) was shown to better describe the observations on route-dependent morphine glucuronidation in the rat small intestine than a traditional physiologically-based model. These theoretical models were expanded, as the segmental segregated flow model and the segmental traditional model, to view the intestine as three segments of equal lengths receiving equal flows to accommodate heterogeneities in segmental transporter and metabolic functions. The influence of heterogeneity in absorptive, exsorptive, and metabolic functions on drug clearance, bioavailability (F), and metabolite formation after intravenous and oral dosing was examined for the intestine when the tissue was the only organ of removal. Simulations were performed for first-order conditions, when drug partitioned readily (flow-limited distribution) or less readily (membrane-limited distribution) into intestinal tissue, and for different gastrointestinal transit times. The intestinal clearance was found to be inversely related to the rate constant for absorption of a drug that was subjected to secretion and was positively correlated with the metabolic and secretory intrinsic clearances. F was positively correlated with the absorption rate constant but was inversely related to the metabolic and secretory intrinsic clearances. The gastrointestinal transit time decreased metabolite formation, increased clearance, and decreasedF. The simulations further showed that a descending metabolic intrinsic clearance yielded a lower F and an ascending segmental distribution of metabolic intrinsic clearance yielded a higher F.
Footnotes
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↵1 Present Address: Amgen Inc., Small molecule Pharmacokinetics and Drug Metabolism, Amgen Center, Thousand Oaks, CA 91320-1799
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This work was supported by the Canadian Institute for Health Research, Grant MOP36457. Debbie Tam was a recipient of a Natural Sciences and Engineering Research Council summer studentship.
- Abbreviations used are::
- TM
- traditional, physiologically-based model
- SFM
- segregated flow model
- STM
- segmental traditional model
- SSFM
- segmental segregated flow model
- sb
- serosal blood
- enb
- enterocyte blood
- AUCiv and AUCpo
- areas under the curve for intravenous and oral dosing, respectively
- CLd1 and CLd2
- transfer clearances from blood to tissue compartment, and from tissue to blood compartment, respectively
- CLint,m and CLint,sec are the metabolic and secretory intrinsic clearances for the total intestine
- respectively
- CLint,mi and CLint,seci
- metabolic and secretory intrinsic clearances for the ith segment (i = 1, 2, or 3), respectively
- CLiv
- intravenous clearance
- CLGIT
- the gastrointestinal luminal transit clearance for the entire intestine
- CLGITi
- the gastrointestinal luminal transit clearance for the ith segment
- F
- bioavailability
- fQ
- fraction of the total intestinal flow perfusing the enterocyte region
- ka
- absorption rate constant for the intestine
- kai
- absorption rate constant for the ith segment
- Mint
- total amount of metabolite formed, with subscripts p.o. and i.v. further denoting oral and intravenous dosing, respectively
- Minti
- metabolite formation from the ith segment
- Qint
- total blood flow to the intestine
- Ven and Venb
- volumes of the enterocyte layer and the blood to the enterocyte layer, respectively
- Veni and Venbi
- volumes of the enterocyte layer and the blood to the enterocyte layer of the ith segment, respectively
- Vint and Vintb
- volumes of intestinal tissue and intestinal blood for the entire intestine
- Vinti and Vintbi
- volumes of intestinal tissue and intestinal blood for the ith segment
- Vs and Vsb
- volumes of the serosal layer and the blood to the serosal layer, respectively
- Vsi and Vsbi
- volumes of the serosal layer and the blood to the serosal layer of the ith segment, respectively
- Received August 28, 2002.
- Accepted December 17, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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