Tetrazole compounds: the effect of structure and pH on Caco-2 cell permeability.
A tetrazole ring is often used in drug discovery as a replacement for the carboxylic acid group. Previous work indicates that compounds containing a tetrazole moiety show asymmetric permeability in Caco-2 cells characteristic of an efflux transporter substrate. The aim of this study is to determine which transporters are responsible for polarization of transport of tetrazole-containing compounds in Caco-2 cells. Results indicate that only select compounds with tetrazole moieties display asymmetric transport. Three compounds (two commercial drug products and one druglike structure) were selected for further studies. Losartan appears to be primarily a P-glycoprotein (P-gp) substrate, as previously reported, but MRP inhibitors such as MK-571 and rifampicin also affect the difference between apical to basolateral and basolateral to apical transport. Pemirolast and phenyltetrazole derivative C are sensitive to P-gp inhibition, but transport seems to be mediated by one or more of the MRP family of transporters. Additionally, lowering the pH from 7.4 to 4.0 eliminates the polarization of permeability in Caco-2 cells. These studies indicate that some tetrazole compounds are susceptible to efflux, therefore caution should be used when choosing an appropriate functional group to replace carboxylic acids when synthesizing a drug candidate.
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas, USA.
Amber M
AM
Young
Kenneth L
KL
Audus
John
J
Proudfoot
Mehran
M
Yazdanian
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism; D018938:Caco-2 Cells; D002460:Cell Line; D002463:Cell Membrane Permeability; D016764:Cell Polarity; D004285:Dogs; D015195:Drug Design; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019808:Losartan / Q000737:chemistry / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism; D011744:Pyrimidinones / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry / Q000378:metabolism*; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001562:Benzimidazoles; D019808:Losartan; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011725:Pyridines; D011744:Pyrimidinones; D013777:Tetrazoles; C055139:pemirolast