Impact of Drug Transporter Studies on Drug Discovery and Development

Mizuno, Naomi; Niwa, Toshiyuki; Yotsumoto, Yoshihisa; Sugiyama, Yuichi

doi:10.1124/pr.55.3.1

Cited by 455 publications

(295 citation statements)

References 325 publications

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“…Because of their ubiquitous distribution and their wide activity range as transporters of several drugs, the role of Oatp/OATP proteins in drug disposition, bio-distribution and absorption is emerging (van Montfoort et al, 2003;Faber et al, 2003;Mizuno et al, 2003;Gerloff, 2004;Niemi, 2007;Bachmakov et al, 2008). This study presents a framework for similar studies to be carried out in ticks.…”

Section: Discussionmentioning

confidence: 99%

Molecular and biological characterization of the Amblyomma americanum organic anion transporter polypeptide

Mulenga

Khumthong

Chalaire

et al. 2008

Journal of Experimental Biology

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SUMMARYThe organic anion transporting polypeptides (Oatps in rodents and other organism; OATPs in human) are Na + -independent transporters that shuttle a wide range of endogenous and xenobotic amphipathic compounds across plasma membranes. We previously discovered an Amblyomma americanum tick (Aam) Oatp cDNA among genes that were upregulated or induced in ticks that were stimulated to start feeding. In this study, we have characterized a 2860 bp full-length cDNA that encode a 724 amino acid putative protein. Bioinformatics and hydropathy analyses revealed that, in addition to the kazal-type serine proteinase inhibitor motif, AamOatp possess typical features that characterize the Oatp/OATP protein family, including 12 transmembrane (TM) domains, the consensus amino acid motif D-X-RW-(I,V)-GAWW-X-G-(F,L)-L and 11 consensus cysteine residues in the large extracellular domain between TM9 and TM10. AamOatp is constitutively and ubiquitously expressed, as determined by RT-PCR amplification of the transcript, in all organs of ticks that fed for 1-7 days. Analysis of the normalized transcript abundance revealed that from days 1 to 5 of feeding, AamOatp mRNA expression in the midgut (MG) was 60-80-fold higher than levels found in the salivary gland (SG), ovary (OV) and carcass (CA). By contrast, by day 7 of feeding, the AamOatp mRNA was 60-80-fold more strongly expressed in the OV than in the SG, MG and CA. These data strongly indicate that changing physiological needs during the tick feeding process influences transcriptional regulation of AamOatp. Our data also show that RNAi-mediated suppression of the AamOatp caused ticks to obtain smaller blood meals, which consequently resulted in ticks laying fewer eggs. The results are discussed in the context of AamOatp as a potential pharmacological or anti-tick vaccine target.

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Section: Discussionmentioning

confidence: 99%

Molecular and biological characterization of the Amblyomma americanum organic anion transporter polypeptide

Mulenga

Khumthong

Chalaire

et al. 2008

Journal of Experimental Biology

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“…Overviews of several families of drug transporters have been published. Since this field is rapidly expanding, this article can only present a momentary snapshot, and several other (Pritchard and Miller 1993;Burckhardt and Wolff 2000;Kullak-Ublick et al 2000;Ayrton and Morgan 2001;Dean et al 2001;Dresser et al 2001;Borst and Oude Elferink 2002;Russel et al 2002;Burckhardt and Burckhardt 2003;Daniel and Rubio-Aliaga 2003;Hagenbuch and Meier 2003;Mizuno et al 2003;Daniel 2004;Koepsell and Endou 2004;Hediger et al 2004;Pauli-Magnus and Meier 2004, and also reviews in this journal issue, i.e. König et al 2006 andGeyer et al 2006).…”

Section: Molecular Classification Of Slc-drug Transportersmentioning

confidence: 99%

Drug transporters in pharmacokinetics

Petzinger¹,

Geyer²

2006

Naunyn Schmied Arch Pharmacol

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This review deals with the drug transporters allowing drugs to enter and leave cells by carrier-mediated pathways. Emphasis is put on liver transporters but systems in gut, kidney, and blood-brain barrier are mentioned as well. Drug-drug interactions on carriers may provoke significant modification in pharmacokinetics as do carrier gene polymorphisms yielding functional carrier protein mutations. An integrated phase concept should reflect the interplay between drug metabolism and drug transport.

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“…ABC superfamily consists of several genetically related transporters with apparently different biological functions, having prominent membrane transport activities in different tissues/cell types (3). P-glycoprotein (P-gp), the product of multidrug resistance (MDR) gene, is one of the most important members of the ABC superfamily (7). Its highly extensive tissue localization as well as different influx/efflux roles and, more importantly, a wide substrate specificity of different chemical and pharmacological classes cause this transporter to be in a central point of attention in pharmacokinetic studies (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Lack of Evidence for Involvement of P-Glycoprotein in Brain Uptake of the Centrally Acting Analgesic, Tramadol in the Rat

et al. 2012

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-Purpose. Tramadol Hydrochloride is a widely-used centrally acting analgesic drug, which has some features of being a P-gp substrate. The present study evaluates the functional involvement of Pgp in CNS distribution of tramadol. Methods. The possibe involvement of P-glycoprotein in brain distribution of tramadol was evaluated using a pharmacokinetic approach in two groups of Pgp-inhibited and control rats. Six male Sprague-Dawley rats were used in each group to collect plasma and brain at 1, 5, 10, and 30 min following two tramadol doses of 1 and 10 mg/kg. Results. The brain uptake clearances of tramadol in Pgp-inhibited and control rats were 2.47±0.56 and 2.34±0.56 ml min , respectively, for 10 mg/kg dose. The brain-to-plasma concentration ratio (Kp,app) of more than 1 in all the time points following both the high and low dose cases (sometimes more than 3) indicated the brain accumulation of the drug. Linear correlation was found between tramadol dose and both corresponding plasma and brain concentrations, but the presence of a dose-dependency was not confirmed by the data obtained for brain-to-plasma concentration ratio. Conclusion. Considering the results of the previous studies and the present research, it seems that the brain accumulation of tramadol is not affected by P-gp inhibition which implies that there may be some other transport mechanisms involved in BBB transport of tramadol.

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Impact of Drug Transporter Studies on Drug Discovery and Development

Cited by 455 publications

References 325 publications

Molecular and biological characterization of the Amblyomma americanum organic anion transporter polypeptide

Molecular and biological characterization of the Amblyomma americanum organic anion transporter polypeptide

Drug transporters in pharmacokinetics

Lack of Evidence for Involvement of P-Glycoprotein in Brain Uptake of the Centrally Acting Analgesic, Tramadol in the Rat

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