Rafehi, Muhammad

[["dc.bibliographiccitation.firstpage","1507"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","Biomolecules"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Gebauer, Lukas"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.contributor.editor","Krause, Frank"],["dc.date.accessioned","2022-12-01T08:31:36Z"],["dc.date.available","2022-12-01T08:31:36Z"],["dc.date.issued","2022"],["dc.date.updated","2022-11-11T13:12:24Z"],["dc.description.abstract","Stereoselectivity is well known and very pronounced in drug metabolism and receptor binding. However, much less is known about stereoselectivity in drug membrane transport. Here, we characterized the stereoselective cell uptake of chiral phenylethylamine derivatives by human monoamine transporters (NET, DAT, and SERT) and organic cation transporters (OCT1, OCT2, and OCT3). Stereoselectivity differed extensively between closely related transporters. High-affinity monoamine transporters (MATs) showed up to 2.4-fold stereoselective uptake of norepinephrine and epinephrine as well as of numerous analogs. While NET and DAT preferentially transported (S)-norepinephrine, SERT preferred the (R)-enantiomer. In contrast, NET and DAT showed higher transport for (R)-epinephrine and SERT for (S)-epinephrine. Generally, MAT stereoselectivity was lower than expected from their high affinity to several catecholamines and from the high stereoselectivity of some inhibitors used as antidepressants. Additionally, the OCTs differed strongly in their stereoselectivity. While OCT1 showed almost no stereoselective uptake, OCT2 was characterized by a roughly 2-fold preference for most (R)-enantiomers of the phenylethylamines. In contrast, OCT3 transported norphenylephrine and phenylephrine with 3.9-fold and 3.3-fold preference for their (R)-enantiomers, respectively, while the para-hydroxylated octopamine and synephrine showed no stereoselective OCT3 transport. Altogether, our data demonstrate that stereoselectivity is highly transporter-to-substrate specific and highly diverse even between homologous transporters."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)"],["dc.description.sponsorship","research program of the University Medical Center, University of Göttingen"],["dc.description.sponsorship","Open Access Publication Funds of the Göttingen University"],["dc.identifier.doi","10.3390/biom12101507"],["dc.identifier.pii","biom12101507"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/118216"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-621"],["dc.publisher","MDPI"],["dc.relation.eissn","2218-273X"],["dc.rights","CC BY 4.0"],["dc.title","Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","unpublished"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","S0006295221004974"],["dc.bibliographiccitation.firstpage","114871"],["dc.bibliographiccitation.journal","Biochemical Pharmacology"],["dc.bibliographiccitation.volume","197"],["dc.contributor.author","Gebauer, Lukas"],["dc.contributor.author","Arul Murugan, N."],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.contributor.author","Rafehi, Muhammad"],["dc.date.accessioned","2022-01-11T14:07:49Z"],["dc.date.available","2022-01-11T14:07:49Z"],["dc.date.issued","2022"],["dc.identifier.doi","10.1016/j.bcp.2021.114871"],["dc.identifier.pii","S0006295221004974"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/97873"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-507"],["dc.relation.issn","0006-2952"],["dc.title","Molecular basis for stereoselective transport of fenoterol by the organic cation transporters 1 and 2"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","113731"],["dc.bibliographiccitation.journal","Biochemical Pharmacology"],["dc.bibliographiccitation.volume","171"],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Tzvetkov, Mladen Vassilev"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.date.accessioned","2020-10-22T08:56:04Z"],["dc.date.available","2020-10-22T08:56:04Z"],["dc.date.issued","2020"],["dc.description.abstract","Stereoselectivity is well described for receptor binding and enzyme catalysis, but so far has only been scarcely investigated in carrier-mediated membrane transport. We thus studied transport kinetics of racemic (anti)adrenergic drugs by the organic cation transporters OCT1 (wild-type and allelic variants), OCT2, OCT3, MATE1, and MATE2-K with a focus on stereospecificity. OCT1 showed stereoselective uptake with up to 2-fold higher vmax over their corresponding counterpart enantiomers for (R,R)-fenoterol, (R,R)-formoterol, (S)-salbutamol, (S)-acebutolol, and (S)-atenolol. Orciprenaline and etilefrine were also transported stereoselectively. The Km was 2.1-fold and 1.5-fold lower for the (S,S)-enantiomers of fenoterol and formoterol, while no significant difference in Km was seen for the other aforementioned drugs. Common OCT1 variants showed similar enantiopreference to wild-type OCT1, with a few notable exceptions (e.g. a switch in enantiospecificity for fenoterol in OCT1 2 compared to the wild-type). Other cation transporters showed strong differences to OCT1 in stereoselectivity and transport activity: The closely related OCT2 displayed a 20-fold higher vmax for (S,S)-fenoterol compared to (R,R)-fenoterol and OCT2 and OCT3 showed 3.5-fold and 4.6-fold higher vmax for the pharmacologically active (R)-salbutamol over (S)-salbutamol. MATE1 and MATE2-K generally mediated transport with a higher capacity but lower affinity compared to OCT1, with moderate stereoselectivity. Our kinetic studies showed that significant stereoselectivity exists in solute carrier-mediated membrane transport of racemic beta-adrenergic drugs with surprising, and in some instances even opposing, preferences between closely related organic cation transporters. This may be relevant for drug therapy, given the strong involvement of these transporters in hepatic and renal drug elimination."],["dc.identifier.doi","10.1016/j.bcp.2019.113731"],["dc.identifier.pmid","31783011"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/68028"],["dc.language.iso","en"],["dc.relation.eissn","1873-2968"],["dc.relation.issn","0006-2952"],["dc.relation.orgunit","Institut für Klinische Pharmakologie"],["dc.title","Stereoselective cell uptake of adrenergic agonists and antagonists by organic cation transporters"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Frontiers in Pharmacology"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Gebauer, Lukas"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.date.accessioned","2021-02-02T15:45:38Z"],["dc.date.available","2021-02-02T15:45:38Z"],["dc.date.issued","2021"],["dc.description.abstract","Psychostimulants are used therapeutically and for illegal recreational purposes. Many of these are inhibitors of the presynaptic noradrenaline, dopamine, and serotonin transporters (NET, DAT, and SERT). According to their physicochemical properties, some might also be substrates of polyspecific organic cation transporters (OCTs) that mediate uptake in liver and kidneys for metabolism and excretion. OCT1 is genetically highly polymorphic, with strong effects on transporter activity and expression. To study potential interindividual differences in their pharmacokinetics, 18 psychostimulants and hallucinogens were assessed in vitro for transport by different OCTs as well as by the high-affinity monoamine transporters NET, DAT, and SERT. The hallucinogenic natural compound mescaline was found to be strongly transported by wild-type OCT1 with a K m of 24.3 µM and a v max of 642 pmol × mg protein−1 × min−1. Transport was modestly reduced in variants 2 and 7, more strongly reduced in 3 and 4, and lowest in 5 and 6, while 8 showed a moderately increased transport capacity. The other phenylethylamine derivatives methamphetamine, para-methoxymethamphetamine, (-)-ephedrine, and cathine ((+)-norpseudoephedrine), as well as dimethyltryptamine, were substrates of OCT2 with K m values in the range of 7.9–46.0 µM and v max values between 70.7 and 570 pmol × mg protein−1 × min−1. Affinities were similar or modestly reduced and the transport capacities were reduced down to half in the naturally occurring variant A270S. Cathine was found to be a substrate for NET and DAT, with the Km being 21-fold and the v max 10-fold higher for DAT but still significantly lower compared to OCT2. This study has shown that several psychostimulants and hallucinogens are substrates for OCTs. Given the extensive cellular uptake of mescaline by the genetically highly polymorphic OCT1, strong interindividual variation in the pharmacokinetics of mescaline might be possible, which could be a reason for highly variable adverse reactions. The involvement of the polymorphic OCT2 in the renal excretion of several psychostimulants could be one reason for individual differences in toxicity."],["dc.identifier.doi","10.3389/fphar.2020.609811"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/79642"],["dc.language.iso","en"],["dc.notes.intern","DeepGreen Import"],["dc.publisher","Frontiers Media S.A."],["dc.relation.eissn","1663-9812"],["dc.relation.issn","1663-9812"],["dc.rights","http://creativecommons.org/licenses/by/4.0/"],["dc.title","Cellular Uptake of Psychostimulants – Are High- and Low-Affinity Organic Cation Transporters Drug Traffickers?"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1297"],["dc.bibliographiccitation.journal","Frontiers in Pharmacology"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Faltraco, Frank"],["dc.contributor.author","Matthaei, Johannes"],["dc.contributor.author","Prukop, Thomas"],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Grytzmann, Aileen"],["dc.contributor.author","Berger, Ralf Günter"],["dc.contributor.author","Krings, Ulrich"],["dc.contributor.author","Vormfelde, Stefan Viktor"],["dc.contributor.author","Tzvetkov, Mladen Vassilev"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.contributor.author","Blome, Felix G."],["dc.date.accessioned","2020-10-22T08:52:50Z"],["dc.date.available","2020-10-22T08:52:50Z"],["dc.date.issued","2019"],["dc.description.abstract","Tyramine, formed by the decarboxylation of tyrosine, is a natural constituent of numerous food products. As an indirect sympathomimetic, it can have potentially dangerous hypertensive effects. In vitro data indicated that the pharmacokinetics of tyramine possibly depend on the organic cation transporter OCT1 genotype and on the CYP2D6 genotype. Since tyramine is a prototypic substrate of monoamine oxidase A (MAO-A), genetic polymorphisms in MAO-A may also be relevant. The aims of this study were to identify to what extent the interindividual variation in pharmacokinetics and pharmacodynamics of tyramine is determined by genetic polymorphisms in OCT1, CYP2D6, and MAO-A. Beyond that, we wanted to evaluate tyramine as probe drug for the in vivo activity of MAO-A and OCT1. Therefore, the pharmacokinetics, pharmacodynamics, and pharmacogenetics of tyramine were studied in 88 healthy volunteers after oral administration of a 400 mg dose. We observed a strong interindividual variation in systemic tyramine exposure, with a mean AUC of 3.74 min µg/ml and a high mean CL/F ratio of 107 l/min. On average, as much as 76.8% of the dose was recovered in urine in form of the MAO-catalysed metabolite 4-hydroxyphenylacetic acid (4-HPAA), confirming that oxidative deamination by MAO-A is the quantitatively most relevant metabolic pathway. Systemic exposure of 4-HPAA varied only up to 3-fold, indicating no strong heritable variation in peripheral MAO-A activity. Systolic blood pressure increased by more than 10 mmHg in 71% of the volunteers and correlated strongly with systemic tyramine concentration. In less than 10% of participants, individually variable blood pressure peaks by >40 mmHg above baseline were observed at tyramine concentrations of >60 µg/l. Unexpectedly, the functionally relevant polymorphisms in OCT1 and CYP2D6, including the CYP2D6 poor and ultra-rapid metaboliser genotypes, did not significantly affect tyramine pharmacokinetics or pharmacodynamics. Also, the MOA-A genotypes, which had been associated in several earlier studies with neuropsychiatric phenotypes, had no significant effects on tyramine pharmacokinetics or its metabolism to 4-HPAA. Thus, variation in tyramine pharmacokinetics and pharmacodynamics is not explained by obvious genomic variation, and human tyramine metabolism did not indicate the existence of ultra-low or -high MAO-A activity."],["dc.identifier.doi","10.3389/fphar.2019.01297"],["dc.identifier.pmid","31736764"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16579"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/68027"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.publisher","Frontiers Media S.A."],["dc.relation.eissn","1663-9812"],["dc.relation.issn","1663-9812"],["dc.relation.orgunit","Institut für Klinische Pharmakologie"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Highly Variable Pharmacokinetics of Tyramine in Humans and Polymorphisms in OCT1, CYP2D6, and MAO-A"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Frontiers in Pharmacology"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Steimer, Werner"],["dc.contributor.author","Pischa, Konstanze"],["dc.contributor.author","Leucht, Stefan"],["dc.contributor.author","Kullmann, Maria"],["dc.contributor.author","Ouethy, Typhaine"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Matthaei, Johannes"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Tzvetkov, Mladen Vassilev"],["dc.date.accessioned","2021-05-26T07:05:59Z"],["dc.date.available","2021-05-26T07:05:59Z"],["dc.date.issued","2021"],["dc.description.abstract","The tricyclic antidepressant amitriptyline is frequently prescribed but its use is limited by its narrow therapeutic range and large variation in pharmacokinetics. Apart from interindividual differences in the activity of the metabolising enzymes cytochrome P450 (CYP) 2D6 and 2C19, genetic polymorphism of the hepatic influx transporter organic cation transporter 1 (OCT1) could be contributing to interindividual variation in pharmacokinetics. Here, the impact of OCT1 genetic variation on the pharmacokinetics of amitriptyline and its active metabolite nortriptyline was studied in vitro as well as in healthy volunteers and in depressive disorder patients. Amitriptyline and nortriptyline were found to inhibit OCT1 in recombinant cells with IC50 values of 28.6 and 40.4 µM. Thirty other antidepressant and neuroleptic drugs were also found to be moderate to strong OCT1 inhibitors with IC50 values in the micromolar range. However, in 35 healthy volunteers, preselected for their OCT1 genotypes, who received a single dose of 25 mg amitriptyline, no significant effects on amitriptyline and nortriptyline pharmacokinetics could be attributed to OCT1 genetic polymorphism. In contrast, the strong impact of the CYP2D6 genotype on amitriptyline and nortriptyline pharmacokinetics and of the CYP2C19 genotype on nortriptyline was confirmed. In addition, acylcarnitine derivatives were measured as endogenous biomarkers for OCT1 activity. The mean plasma concentrations of isobutyrylcarnitine and 2-methylbutyrylcarnitine were higher in participants with two active OCT1 alleles compared to those with zero OCT1 activity, further supporting their role as endogenous in vivo biomarkers for OCT1 activity. A moderate reduction in plasma isobutyrylcarnitine concentrations occurred at the time points at which amitriptyline plasma concentrations were the highest. In a second, independent study sample of 50 patients who underwent amitriptyline therapy of 75 mg twice daily, a significant trend of increasing amitriptyline plasma concentrations with decreasing OCT1 activity was observed (p = 0.018), while nortriptyline plasma concentrations were unaffected by the OCT1 genotype. Altogether, this comprehensive study showed that OCT1 activity does not appear to be a major factor determining amitriptyline and nortriptyline pharmacokinetics and that hepatic uptake occurs mainly through other mechanisms."],["dc.identifier.doi","10.3389/fphar.2021.688950"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/84733"],["dc.language.iso","en"],["dc.notes.intern","DeepGreen Import"],["dc.publisher","Frontiers Media S.A."],["dc.relation.eissn","1663-9812"],["dc.relation.issn","1663-9812"],["dc.rights","CC BY 4.0"],["dc.title","Effects of Genetic Polymorphism in CYP2D6, CYP2C19, and the Organic Cation Transporter OCT1 on Amitriptyline Pharmacokinetics in Healthy Volunteers and Depressive Disorder Patients"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]