Abstract
The aim of this study was to investigate the effect of ionization on drug transport across the intestinal epithelium in order to include this effect in structure-absorption relationships. The pH-dependent permeation of one rapidly (alfentanil) and one slowly (cimetidine) transported basic model drug across Caco-2 cell monolayers was investigated. Both drugs had pKavalues in the physiological pH range. The permeability coefficients (Pc) of the model drugs were obtained at varying apical buffer pHs, thus varying the degree of drug ionization (from 5 to 95%). The relationship between Pc and the fraction of the drug in un-ionized form (fu) was analyzed to delineate the permeability coefficients of the un-ionized (Pc,u) and ionized (Pc,i) forms of the drugs. Theoretical estimates of the pKa values were also calculated from ionization energies for each model compound. For both drugs, a linear increase in Pc was observed with increasing fu. Transport of the un-ionized form was 150- and 30-fold more rapid than transport of the ionized form for alfentanil and cimetidine, respectively. However, when fu < 0.1, the contribution of the ionized form was significant. Because fu is <0.1 over the entire physiological pH range for a large number of drugs, these results will have implications on predictions of in vivo intestinal drug absorption both from in vitro studies in cell cultures and from computed structural properties of drug molecules.
Footnotes
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Send reprint requests to: Per Artursson, Department of Pharmacy, Box 580, Uppsala University, SE-751 23 Uppsala, Sweden. E-mail: per.artursson{at}galenik.uu.se
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↵1 This work was supported by Grant 95–98 from Centrala Försöksdjursnämnden, Grant 9478 from The Swedish Medical Research Council, Grant K11163-302 from The Swedish Natural Science Research Council, and The Swedish Fund for Scientific Research without Animals.
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↵2 Present address: Department of Internal Medicine, University Hospital Groningen, Groningen, the Netherlands.
- Abbreviations:
- Pc
- permeability coefficient of the cell monolayer
- fu
- fraction of drug in un-ionized form
- Pc,u
- cell monolayer permeability coefficient of the un-ionized form
- Pc,i
- cell monolayer permeability coefficient of the ionized form
- HBSS
- Hanks’ balanced salt solution
- a-b
- apical-to-basolateral
- b-a
- basolateral-to-apical
- Papp
- apparent permeability coefficient
- CD
- concentration in the donor compartment
- CR
- concentration in the receiver compartment
- fi
- fraction of drug in ionized form
- MES
- 2-(N-morpholino)ethanesulfonic acid
- Received March 8, 1999.
- Accepted June 2, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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