In vitro substrate identification studies for P-glycoprotein-mediated transport

Species difference and predictability of in vivo results

Masayo Yamazaki, William E. Neway, Tomoyuki Ohe, I. Wu Chen, Janice F. Rowe, Jerome H. Hochman, Masato Chiba, Jiunn H. Lin

Research output: Contribution to journalArticle

214 Citations (Scopus)

Abstract

Two different cellular assay models were assessed as in vitro systems for P-glycoprotein (P-gp) substrate identification: cellular accumulation studies with KB-V1, a human MDR1 P-gp-overexpressing multidrug-resistant human epidermoid carcinoma cell line; and transcellular transport studies with L-MDR1 (or L-mdr1a), a human MDR1 (or mouse mdr1a)-transfected porcine renal epithelial cell line. The in vitro-in vivo correlation for P-gp-mediated transport activity was also examined by comparing in vitro data obtained from L-mdr1a cell studies and in vivo data from mdr1a (-/-)/(+/+) CF-1 mice studies for several compounds. The results are summarized as follows: 1) two in vitro assay systems routinely identified the substrate for human MDR1 P-gp-mediated transport with similar quantitative results; 2) in vitro studies with L-MDR1 and L-mdr1a cells demonstrated that the P-gp substrate susceptibility is different between human and mouse for certain compounds (species difference); and 3) in vivo brain concentration ratios of mdr1a (-/-) to (+/+) CF-1 mice, either at a certain time point or up to 60 min, correlated well with the in vitro transcellular transport ratios from L-mdr1a cells (r2 = 0.968 and 0.926, respectively). This indicates that, at least in mice, the in vitro data are valid predictors of the in vivo contribution of P-gp: the contribution of P-gp to the distribution of the compound to the brain up to 60 min post i.v. administration. These results provide a rationale for predicting in vivo relevance of P-gp in human form in vitro data using human P-gp-expressing cells.

Original languageEnglish
Pages (from-to)723-735
Number of pages13
JournalJournal of Pharmacology and Experimental Therapeutics
Volume296
Issue number3
Publication statusPublished - 2001
Externally publishedYes

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P-Glycoprotein
Transcytosis
In Vitro Techniques
Cell Line
Brain
Squamous Cell Carcinoma
Swine
Epithelial Cells
Kidney

ASJC Scopus subject areas

  • Pharmacology

Cite this

In vitro substrate identification studies for P-glycoprotein-mediated transport : Species difference and predictability of in vivo results. / Yamazaki, Masayo; Neway, William E.; Ohe, Tomoyuki; Chen, I. Wu; Rowe, Janice F.; Hochman, Jerome H.; Chiba, Masato; Lin, Jiunn H.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 296, No. 3, 2001, p. 723-735.

Research output: Contribution to journalArticle

Yamazaki, Masayo ; Neway, William E. ; Ohe, Tomoyuki ; Chen, I. Wu ; Rowe, Janice F. ; Hochman, Jerome H. ; Chiba, Masato ; Lin, Jiunn H. / In vitro substrate identification studies for P-glycoprotein-mediated transport : Species difference and predictability of in vivo results. In: Journal of Pharmacology and Experimental Therapeutics. 2001 ; Vol. 296, No. 3. pp. 723-735.
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