Pitavastatin as an In Vivo Probe for Studying Hepatic Organic Anion Transporting Polypeptide-Mediated Drug–Drug Interactions in Cynomolgus Monkeys

2013 ◽  
Vol 41 (10) ◽  
pp. 1875-1882 ◽  
Author(s):  
Tsuyoshi Takahashi ◽  
Tatsuyuki Ohtsuka ◽  
Takahiro Yoshikawa ◽  
Ichiro Tatekawa ◽  
Yasuhiro Uno ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Cynomolgus Monkeys ◽  
Organic Anion Transporting Polypeptide

scholarly journals In Vitro Interaction of AB-FUBINACA with Human Cytochrome P450, UDP-Glucuronosyltransferase Enzymes and Drug Transporters

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4589 ◽  
Author(s):  
Sunjoo Kim ◽  
Dong Kyun Kim ◽  
Yongho Shin ◽  
Ji-Hyeon Jeon ◽  
Im-Sook Song ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Liver Microsomes ◽  
Drug Abusers ◽  
Cancer Resistance ◽  
Mixed Inhibition ◽  
P Glycoprotein ◽  
Human Cytochrome

AB-FUBINACA, a synthetic indazole carboxamide cannabinoid, has been used worldwide as a new psychoactive substance. Because drug abusers take various drugs concomitantly, it is necessary to explore potential AB-FUBINACA-induced drug–drug interactions caused by modulation of drug-metabolizing enzymes and transporters. In this study, the inhibitory effects of AB-FUBINACA on eight major human cytochrome P450s (CYPs) and six uridine 5′-diphospho-glucuronosyltransferases (UGTs) of human liver microsomes, and on eight clinically important transport activities including organic cation transporters (OCT)1 and OCT2, organic anion transporters (OAT)1 and OAT3, organic anion transporting polypeptide transporters (OATP)1B1 and OATP1B3, P-glycoprotein, and breast cancer resistance protein (BCRP) in transporter-overexpressing cells were investigated. AB-FUBINACA inhibited CYP2B6-mediated bupropion hydroxylation via mixed inhibition with Ki value of 15.0 µM and competitively inhibited CYP2C8-catalyzed amodiaquine N-de-ethylation, CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP2C19-catalyzed [S]-mephenytoin 4′-hydroxylation, and CYP2D6-catalyzed bufuralol 1′-hydroxylation with Ki values of 19.9, 13.1, 6.3, and 20.8 µM, respectively. AB-FUBINACA inhibited OCT2-mediated MPP+ uptake via mixed inhibition (Ki, 54.2 µM) and competitively inhibited OATP1B1-mediated estrone-3-sulfate uptake (Ki, 94.4 µM). However, AB-FUBINACA did not significantly inhibit CYP1A2, CYP2A6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A6, or UGT2B7 enzyme activities at concentrations up to 100 µM. AB-FUBINACA did not significantly inhibit the transport activities of OCT1, OAT1/3, OATP1B3, P-glycoprotein, or BCRP at concentrations up to 250 μM. As the pharmacokinetics of AB-FUBINACA in humans and animals remain unknown, it is necessary to clinically evaluate potential in vivo pharmacokinetic drug–drug interactions induced by AB-FUBINACA-mediated inhibition of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, OCT2, and OATP1B1 activities.

Substrate specificities of rat oatp1 and ntcp: implications for hepatic organic anion uptake

2003 ◽  
Vol 285 (5) ◽  
pp. G829-G839 ◽  
Author(s):  
Soichiro Hata ◽  
Pijun Wang ◽  
Nicole Eftychiou ◽  
Meenakshisundaram Ananthanarayanan ◽  
Ashok Batta ◽  
...  
Keyword(s):  
Bile Acids ◽  
Competitive Inhibition ◽  
Organic Anion ◽  
Inducible Promoter ◽  
Hydroxyl Groups ◽  
Organic Anion Transporting Polypeptide ◽  
Hela Cell Lines ◽  
Dependent Transport

Transport of a series of3H-radiolabeled C23, C24, and C27bile acid derivatives was compared and contrasted in HeLa cell lines stably transfected with rat Na+/taurocholate cotransporting polypeptide (ntcp) or organic anion transporting polypeptide 1 (oatp1) in which expression was under regulation of a zinc-inducible promoter. Similar uptake patterns were observed for both ntcp and oatp1, except that unconjugated hyodeoxycholate was a substrate of oatp1 but not ntcp. Conjugated bile acids were transported better than nonconjugated bile acids, and the configuration of the hydroxyl groups (α or β) had little influence on uptake. Although cholic and 23 norcholic acids were transported by ntcp and oatp1, other unconjugated bile acids (chenodeoxycholic, ursodeoxycholic) were not. In contrast to ntcp, oatp1-mediated uptake of the trihydroxy bile acids taurocholate and glycocholate was four- to eightfold below that of the corresponding dihydroxy conjugates. Ntcp mediated high affinity, sodium-dependent transport of [35S]sulfobromophthalein with a Kmsimilar to that of oatp1-mediated transport of [35S]sulfobromophthalein ( Km= 3.7 vs. 3.3 μM, respectively). In addition, for both transporters, uptake of sulfobromophthalein and taurocholic acid showed mutual competitive inhibition. These results indicate that the substrate specificity of ntcp is considerably broader than previously suspected and caution the extrapolation of transport data obtained in vitro to physiological function in vivo.

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