tetracycline and estrone-sulfate

Organic anion-transporting polypeptides (human OATPs; animals Oatps; gene symbol SLCO/Slco) are integral membrane proteins that mediate the sodium-independent transport of a wide range of endogenous compounds as well as many xenobiotics. Antibiotics, antidiabetic drugs, anti-inflammatory drugs, antifungals, antivirals, antihistamines, antihypertensives, fibrates, statins, cardiac glycosides, immunosuppressants, and anticancer drugs are among the substrates transported by OATPs. Because of the broad substrate specificity, wide tissue distribution and the involvement of drug-drug interaction, human OATPs have been extensively recognized as key determinants for drug absorption, distribution and excretion. In a previous study, we cloned a functional orthologue of human OATP1A2 from the pig liver and designated it as swine Oatp1a2 (sOatp1a2) based on sequence analysis and phylogenic study. In the present study, transport capability of swine Oatp1a2 for tetracyclines, macrolides and β-lactam antibiotics was investigated. It was found that most of the tested antibiotics, including the tetracycline family members such as tetracycline, doxycycline, oxytetracycline and chlortetracycline as well as the β-lactam antibiotics such as penicillin, amoxicillin and cefquinome are directly transported by sOatp1a2; while macrolides such as tylosin, tilmicosin, clarithromycin and erythromycin may only inhibit uptake function of the transporter. As a group of well-known inhibitors of OATP family members, the effect of flavonoids on sOatp1a2 function was evaluated and it was found that all the flavonoids tested are inhibitors of the swine transporter as well.

Topics: Animals; Anti-Bacterial Agents; beta-Lactams; Dose-Response Relationship, Drug; Drug Interactions; Estrone; Flavonoids; Gas Chromatography-Mass Spectrometry; HEK293 Cells; Humans; Macrolides; Organic Anion Transporters; Swine; Taurocholic Acid; Tetracycline

The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.

Topics: Atorvastatin; Biological Transport; Drug Interactions; Estradiol; Estrone; HEK293 Cells; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro Techniques; Least-Squares Analysis; Liver; Liver-Specific Organic Anion Transporter 1; Models, Molecular; Multivariate Analysis; Organic Anion Transporters; Organic Anion Transporters, Sodium-Independent; Protein Isoforms; Pyrroles; Solute Carrier Organic Anion Transporter Family Member 1B3; Structure-Activity Relationship; Transfection

We succeeded in isolating a novel organic solute carrier from a human placenta cDNA library. The isolated cDNA consisted of 1137 base pairs that encoded a 379-amino acid protein, hOSCP1. Northern blot and reverse transcription PCR analyses revealed that the hOSCP1 mRNA is expressed in the placenta and testis and weakly expressed in the thymus and small intestine. When expressed in Xenopus laevis oocytes, hOSCP1 mediated the high affinity transport of p-aminohippurate (PAH) (K(m) = 35.0 +/- 7.5 microm) and tetraethylammonium (K(m) = 62.3 +/- 12.2 microm) in a sodium-independent manner. However, the hOSCP1-expressing oocyte did not mediate the transport of L-carnitine. The transport of PAH by hOSCP1 was sensitive to pH, but the tetraethylammonium was not transported at the high pH examined. hOSCP1 transported prostaglandin E(2), prostaglandin F(2alpha), estrone sulfate, glutarate, L-leucine, L-ascorbic acid, and tetracycline. Thus, hOSCP1 also showed broad substrate specificity. A wide range of structurally unrelated organic compounds inhibited the hOSCP1-mediated PAH uptake. Immunohistochemical analysis revealed that the hOSCP1 protein is localized in the basal membrane of the syncytiotrophoblast in the human placenta. Our results suggest that hOSCP1 is a novel polyspecific organic solute carrier protein responsible for drug clearance from the human placenta.

Topics: Amino Acid Sequence; Animals; Ascorbic Acid; Biological Transport; Blotting, Northern; Cell Line, Tumor; Dinoprost; Dinoprostone; DNA, Complementary; Dose-Response Relationship, Drug; Estrone; Female; Gene Library; Genes, Tumor Suppressor; Glutarates; Humans; Hydrogen-Ion Concentration; Immunohistochemistry; Intestine, Small; Kinetics; Leucine; Male; Membrane Transport Proteins; Mice; Molecular Sequence Data; Oocytes; p-Aminohippuric Acid; Phylogeny; Placenta; Regression Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Complementary; RNA, Messenger; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Sodium; Substrate Specificity; Testis; Tetracycline; Tetraethylammonium; Thymus Gland; Tissue Distribution; Trophoblasts; Xenopus laevis