The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Mikko Niemi - One of the best experts on this subject based on the ideXlab platform.
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Organic Anion Transporting Polypeptide 1B1: a Genetically Polymorphic Transporter of Major Importance for Hepatic Drug Uptake
Pharmacological Reviews, 2011Co-Authors: Mikko Niemi, Marja K. PasanenAbstract:The importance of membrane transporters for Drug pharmacokinetics has been increasingly recognized during the last decade. Organic anion transporting polypeptide 1B1 (OATP1B1) is a genetically polymorphic influx transporter expressed on the sinusoidal membrane of human hepatocytes, and it mediates the hepatic Uptake of many endogenous compounds and xenobiotics. Recent studies have demonstrated that OATP1B1 plays a major, clinically important role in the hepatic Uptake of many Drugs. A common single-nucleotide variation (coding DNA c.521T>C, protein p.V174A, rs4149056) in the SLCO1B1 gene encoding OATP1B1 decreases the transporting activity of OATP1B1, resulting in markedly increased plasma concentrations of, for example, many statins, particularly of active simvastatin acid. The variant thereby enhances the risk of statin-induced myopathy and decreases the therapeutic indexes of statins. However, the effect of the SLCO1B1 c.521T>C variant is different on different statins. The same variant also markedly affects the pharmacokinetics of several other Drugs. Furthermore, certain SLCO1B1 variants associated with an enhanced clearance of methotrexate increase the risk of gastrointestinal toxicity by methotrexate in the treatment of children with acute lymphoblastic leukemia. Certain Drugs (e.g., cyclosporine) potently inhibit OATP1B1, causing clinically significant Drug interactions. Thus, OATP1B1 plays a major role in the hepatic Uptake of Drugs, and genetic variants and Drug interactions affecting OATP1B1 activity are important determinants of individual Drug responses. In this article, we review the current knowledge about the expression, function, substrate characteristics, and pharmacogenetics of OATP1B1 as well as its role in Drug interactions, in parts comparing with those of other hepatocyte-expressed organic anion transporting polypeptides, OATP1B3 and OATP2B1.
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Frequencies of single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide 1B1 SLCO1B1 gene in a Finnish population.
European Journal of Clinical Pharmacology, 2006Co-Authors: Marja K. Pasanen, Janne T. Backman, Mikko NiemiAbstract:Objective Organic anion transporting polypeptide 1B1 (OATP1B1) is a Drug Uptake transporter located at the sinusoidal membrane of hepatocytes. Our aim was to establish high-throughput genotyping assays for the major known single nucleotide polymorphisms (SNP) in the SLCO1B1 gene encoding OATP1B1 and to investigate the frequencies of SNPs and haplotypes of SLCO1B1 in a large Caucasian population.
Marja K. Pasanen - One of the best experts on this subject based on the ideXlab platform.
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Organic Anion Transporting Polypeptide 1B1: a Genetically Polymorphic Transporter of Major Importance for Hepatic Drug Uptake
Pharmacological Reviews, 2011Co-Authors: Mikko Niemi, Marja K. PasanenAbstract:The importance of membrane transporters for Drug pharmacokinetics has been increasingly recognized during the last decade. Organic anion transporting polypeptide 1B1 (OATP1B1) is a genetically polymorphic influx transporter expressed on the sinusoidal membrane of human hepatocytes, and it mediates the hepatic Uptake of many endogenous compounds and xenobiotics. Recent studies have demonstrated that OATP1B1 plays a major, clinically important role in the hepatic Uptake of many Drugs. A common single-nucleotide variation (coding DNA c.521T>C, protein p.V174A, rs4149056) in the SLCO1B1 gene encoding OATP1B1 decreases the transporting activity of OATP1B1, resulting in markedly increased plasma concentrations of, for example, many statins, particularly of active simvastatin acid. The variant thereby enhances the risk of statin-induced myopathy and decreases the therapeutic indexes of statins. However, the effect of the SLCO1B1 c.521T>C variant is different on different statins. The same variant also markedly affects the pharmacokinetics of several other Drugs. Furthermore, certain SLCO1B1 variants associated with an enhanced clearance of methotrexate increase the risk of gastrointestinal toxicity by methotrexate in the treatment of children with acute lymphoblastic leukemia. Certain Drugs (e.g., cyclosporine) potently inhibit OATP1B1, causing clinically significant Drug interactions. Thus, OATP1B1 plays a major role in the hepatic Uptake of Drugs, and genetic variants and Drug interactions affecting OATP1B1 activity are important determinants of individual Drug responses. In this article, we review the current knowledge about the expression, function, substrate characteristics, and pharmacogenetics of OATP1B1 as well as its role in Drug interactions, in parts comparing with those of other hepatocyte-expressed organic anion transporting polypeptides, OATP1B3 and OATP2B1.
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Frequencies of single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide 1B1 SLCO1B1 gene in a Finnish population.
European Journal of Clinical Pharmacology, 2006Co-Authors: Marja K. Pasanen, Janne T. Backman, Mikko NiemiAbstract:Objective Organic anion transporting polypeptide 1B1 (OATP1B1) is a Drug Uptake transporter located at the sinusoidal membrane of hepatocytes. Our aim was to establish high-throughput genotyping assays for the major known single nucleotide polymorphisms (SNP) in the SLCO1B1 gene encoding OATP1B1 and to investigate the frequencies of SNPs and haplotypes of SLCO1B1 in a large Caucasian population.
David G Bailey - One of the best experts on this subject based on the ideXlab platform.
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effect of Drug transporter genotypes on pravastatin disposition in european and african american participants
Pharmacogenetics and Genomics, 2007Co-Authors: Leena Choi, Ute I. Schwarz, David G Bailey, Wooin Lee, Gail Mayo, Rommel G Tirona, Michael C Stein, Richard B KimAbstract:Objective Our aims were to evaluate the effects of polymorphisms in the hepatic Drug Uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1, SLCO1B1) and efflux transporters multiDrug resistance-associated protein 2 (MRP2, ABCC2), bile salt export pump (BSEP, ABCB11), and breast cancer-related protein (BCRP, ABCG2) on single-dose pravastatin pharmacokinetics in healthy European- and African-American participants.
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intestinal Drug transporter expression and the impact of grapefruit juice in humans
Clinical Pharmacology & Therapeutics, 2007Co-Authors: David G Bailey, Hartmut Glaeser, G K Dresser, J C Gregor, U I Schwarz, J S Mcgrath, E JolicoeurAbstract:The goals of this study were to assess the extent of human intestinal Drug transporter expression, determine the subcellular localization of the Drug Uptake transporter OATP1A2, and then to assess the effect of grapefruit juice consumption on OATP1A2 expression relative to cytochrome P450 3A4 and MDR1. Expression of Drug Uptake and efflux transporters was assessed using human duodenal biopsy samples. Fexofenadine Uptake by different transporters was measured in a transporter-transfected cell line. We investigated the influence of grapefruit juice on pharmacokinetics of orally administered fexofenadine. The effect of grapefruit juice on the expression of intestinal transporters was determined using real-time polymerase chain reaction and Western blot analysis. In the duodenum of healthy volunteers, an array of CYP enzymes as well as Uptake and efflux transporters was expressed. Importantly, Uptake transporters thought to be liver-specific, such as OATP1B1 and 1B3, as well as OATP2B1 and 1A2 were expressed in the intestine. However, among OATP transporters, only OATP1A2 was capable of fexofenadine Uptake when assessed in vitro. OATP1A2 colocalized with MDR1 to the brush border domain of enterocytes. Consumption of grapefruit juice concomitantly or 2 h before fexofenadine administration was associated with reduced oral fexofenadine plasma exposure, whereas intestinal expression of either OATP1A2 or MDR1 remained unaffected. In conclusion, an array of Drug Uptake and efflux transporters are expressed in the human intestine. OATP1A2 is likely the key intestinal Uptake transporter for fexofenadine absorption whose inhibition results in the grapefruit juice effect. Although short-term grapefruit juice ingestion was associated with reduced fexofenadine availability, OATP1A2 or MDR1 expression was unaffected.
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fruit juices inhibit organic anion transporting polypeptide mediated Drug Uptake to decrease the oral availability of fexofenadine
Clinical Pharmacology & Therapeutics, 2002Co-Authors: Brenda F. Leake, George K Dresser, David G Bailey, Ute I. SchwarzAbstract:Objectives Our objective was to examine the effect of different fruits and their constituents on P-glycoprotein and organic anion transporting polypeptide (OATP) activities in vitro and on Drug disposition in humans. Methods P-glycoprotein–mediated digoxin or vinblastine efflux was determined in polarized epithelial cell monolayers. OATP-mediated fexofenadine Uptake was measured in a transfected cell line. The oral pharmacokinetics of 120 mg fexofenadine was assessed with water, 25%-strength grapefruit juice, or normal-strength grapefruit, orange, or apple juices (1.2 L over 3 hours) in a randomized 5-way crossover study in 10 healthy subjects. Results Grapefruit juice and segments and apple juice at 5% of normal strength did not alter P-glycoprotein activity. Grapefruit extract reduced transport. 6′,7′-Dihydroxybergamottin had modest inhibitory activity (50% inhibitory concentration [IC50], 33 μmol/L). In contrast, grapefruit, orange, and apple juices at 5% of normal strength markedly reduced human OATP and rat oatp activity. 6′,7′-Dihydroxybergamottin potently inhibited rat oatp3 and oatp1 (IC50, 0.28 μmol/L). Other furanocoumarins and bioflavonoids also reduced rat oatp3 activity. Grapefruit, orange, and apple juices decreased the fexofenadine area under the plasma concentration–time curve (AUC), the peak plasma Drug concentration (Cmax), and the urinary excretion values to 30% to 40% of those with water, with no change in the time to reach Cmax, elimination half-life, renal clearance, or urine volume in humans. Change in fexofenadine AUC with juice was variable among individuals and inversely dependent on value with water. Conclusions Fruit juices and constituents are more potent inhibitors of OATPs than P-glycoprotein activities, which can reduce oral Drug bioavailability. Results support a new model of intestinal Drug absorption and mechanism of food-Drug interaction. Clinical Pharmacology & Therapeutics (2002) 71, 11–20; doi: 10.1067/mcp.2002.121152
Conor L Evans - One of the best experts on this subject based on the ideXlab platform.
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visualizing topical Drug Uptake with conventional fluorescence microscopy and deep learning
Biomedical Optics Express, 2020Co-Authors: Conor L Evans, Maiko Hermsmeier, Akira Yamamoto, Kin F ChanAbstract:Mapping the Uptake of topical Drugs and quantifying dermal pharmacokinetics (PK) presents numerous challenges. Though high resolution and high precision methods such as mass spectrometry offer the means to quantify Drug concentration in tissue, these tools are complex and often expensive, limiting their use in routine experiments. For the many topical Drugs that are naturally fluorescent, tracking fluorescence emission can be a means to gather critical PK parameters. However, skin autofluorescence can often overwhelm Drug fluorescence signatures. Here we demonstrate the combination of standard epi-fluorescence imaging with deep learning for the visualization and quantification of fluorescent Drugs in human skin. By training a U-Net convolutional neural network on a dataset of annotated images, Drug Uptake from both high "infinite" dose and daily clinical dose regimens can be measured and quantified. This approach has the potential to simplify routine topical product development in the laboratory.
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visualization of Drug distribution of a topical minocycline gel in human facial skin
Biomedical Optics Express, 2018Co-Authors: Sinyoung Jeong, Maiko Hermsmeier, Akira Yamamoto, Kin F Chan, Sam Osseiran, Usha Nagavarapu, Conor L EvansAbstract:Acne vulgaris is a common chronic skin disease in young adults caused by infection of the pilosebaceous unit, resulting in pimples and possibly permanent scarring on the skin. Minocycline, a common antibiotic, has been widely utilized as a systemic antimicrobial treatment for acne via oral administration. Recently, a topical minocycline gel (BPX-01) was developed to directly deliver minocycline through the epidermis and into the pilosebaceous unit to achieve localized treatment with lower doses of Drug. As the effectiveness of the Drug is directly related to its successful delivery, there is a need to evaluate the pharmacokinetics at the cellular level within tissue. Advantageously, minocycline is naturally fluorescent and can be directly visualized using microscopy-based approaches. Due to high endogenous autofluorescence, however, imaging of weakly emitting fluorescent molecules such as minocycline in skin tissue can be challenging. Here, we demonstrate a method for the selective visualization of minocycline within human skin tissue by utilizing two-photon excitation fluorescence (TPEF) microscopy and fluorescence lifetime imaging microscopy (FLIM). To demonstrate the feasibility of this approach, ex vivo human facial skin samples treated with various concentrations of BPX-01 were investigated. From the TPEF analysis, we were able to visualize relatively high levels of Drug Uptake within facial skin. However, minocycline fluorescence could be overwhelmed by endogenous fluorescence that complicates TPEF quantitative analysis, making FLIM more advantageous for visualizing Drug Uptake. Importantly, we found a unique signature of minocycline Uptake via FLIM analysis that enabled the successful differentiation of the Drug and enabled the extraction of Drug local distribution from the endogenous fluorescence using a non-Euclidean phasor analysis method. Based on these results, we believe that the Drug local distribution visualization method using TPEF and FLIM with phasor analysis can play an important role in studying the pharmacokinetics and pharmacodynamics of a topically applicable Drug.
Kin F Chan - One of the best experts on this subject based on the ideXlab platform.
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visualizing topical Drug Uptake with conventional fluorescence microscopy and deep learning
Biomedical Optics Express, 2020Co-Authors: Conor L Evans, Maiko Hermsmeier, Akira Yamamoto, Kin F ChanAbstract:Mapping the Uptake of topical Drugs and quantifying dermal pharmacokinetics (PK) presents numerous challenges. Though high resolution and high precision methods such as mass spectrometry offer the means to quantify Drug concentration in tissue, these tools are complex and often expensive, limiting their use in routine experiments. For the many topical Drugs that are naturally fluorescent, tracking fluorescence emission can be a means to gather critical PK parameters. However, skin autofluorescence can often overwhelm Drug fluorescence signatures. Here we demonstrate the combination of standard epi-fluorescence imaging with deep learning for the visualization and quantification of fluorescent Drugs in human skin. By training a U-Net convolutional neural network on a dataset of annotated images, Drug Uptake from both high "infinite" dose and daily clinical dose regimens can be measured and quantified. This approach has the potential to simplify routine topical product development in the laboratory.
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visualization of Drug distribution of a topical minocycline gel in human facial skin
Biomedical Optics Express, 2018Co-Authors: Sinyoung Jeong, Maiko Hermsmeier, Akira Yamamoto, Kin F Chan, Sam Osseiran, Usha Nagavarapu, Conor L EvansAbstract:Acne vulgaris is a common chronic skin disease in young adults caused by infection of the pilosebaceous unit, resulting in pimples and possibly permanent scarring on the skin. Minocycline, a common antibiotic, has been widely utilized as a systemic antimicrobial treatment for acne via oral administration. Recently, a topical minocycline gel (BPX-01) was developed to directly deliver minocycline through the epidermis and into the pilosebaceous unit to achieve localized treatment with lower doses of Drug. As the effectiveness of the Drug is directly related to its successful delivery, there is a need to evaluate the pharmacokinetics at the cellular level within tissue. Advantageously, minocycline is naturally fluorescent and can be directly visualized using microscopy-based approaches. Due to high endogenous autofluorescence, however, imaging of weakly emitting fluorescent molecules such as minocycline in skin tissue can be challenging. Here, we demonstrate a method for the selective visualization of minocycline within human skin tissue by utilizing two-photon excitation fluorescence (TPEF) microscopy and fluorescence lifetime imaging microscopy (FLIM). To demonstrate the feasibility of this approach, ex vivo human facial skin samples treated with various concentrations of BPX-01 were investigated. From the TPEF analysis, we were able to visualize relatively high levels of Drug Uptake within facial skin. However, minocycline fluorescence could be overwhelmed by endogenous fluorescence that complicates TPEF quantitative analysis, making FLIM more advantageous for visualizing Drug Uptake. Importantly, we found a unique signature of minocycline Uptake via FLIM analysis that enabled the successful differentiation of the Drug and enabled the extraction of Drug local distribution from the endogenous fluorescence using a non-Euclidean phasor analysis method. Based on these results, we believe that the Drug local distribution visualization method using TPEF and FLIM with phasor analysis can play an important role in studying the pharmacokinetics and pharmacodynamics of a topically applicable Drug.
