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Role of intestinal P‐glycoprotein ( mdr1 ) in interpatient variation in the oral bioavailability of cyclosporine
Author(s) -
Lown Kenneth S.,
Mayo Robert R.,
Leichtman Alan B.,
Hsiao Hsiuling,
Turgeon D. Kim,
SchmiedlinRen Phyllissa,
Brown Morton B.,
Guo Wensheng,
Rossi Stephen J.,
Benet Leslie Z.,
Watkins Paul B.
Publication year - 1997
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(97)90027-8
Subject(s) - cyp3a4 , p glycoprotein , pharmacokinetics , ciclosporin , bioavailability , pharmacology , oral administration , medicine , chemistry , glycoprotein , orosomucoid , endocrinology , kidney , metabolism , biochemistry , cytochrome p450 , antibiotics , multiple drug resistance
Interpatient differences in the oral clearance of cyclosporine (INN, ciclosporin) have been partially attributed to variation in the activity of a single liver enzyme termed CYP3A4. Recently it has been shown that small bowel also contains CYP3A4, as well as P‐glycoprotein, a protein able to transport cyclosporine. To assess the importance of these intestinal proteins, the oral pharmacokinetics of cyclosporine were measured in 25 kidney transplant recipients who each had their liver CYP3A4 activity quantitated by the intravenous [ 14 C‐ N ‐methyl]‐erythromycin breath test and who underwent small bowel biopsy for measurement of CYP3A4 and P‐glycoprotein. Forward multiple regression revealed that 56% (i.e., r 2 = 0.56) and 17% of the variability in apparent oral clearance [log (dose/area under the curve)] were accounted for by variation in liver CYP3A4 activity ( p < 0.0001) and intestinal P‐glycoprotein concentration ( p = 0.0059), respectively. For peak blood concentration, liver CYP3A4 activity accounted for 32% ( p = 0.0002) and P‐glycoprotein accounted for an additional 30% ( p = 0.0024) of the variability. Intestinal levels of CYP3A4, which varied tenfold, did not appear to influence any cyclosporine pharmacokinetic parameter examined. We conclude that intestinal P‐glycoprotein plays a significant role in the first‐pass elimination of cyclosporine, presumably by being a rate‐limiting step in absorption. Drug interactions with cyclosporine previously ascribed to intestinal CYP3A4 may instead be mediated by interactions with intestinal P‐glycoprotein. Clinical Pharmacology & Therapeutics (1997) 62 , 248–260; doi: