Bedeutung genetischer Polymorphismen im organischen Kationentransporter OCT1 für die Pharmakokinetik und Nebenwirkungen von Proguanil

Tann, Annabelle

dc.contributor.advisor	Brockmöller, Jürgen Prof. Dr.
dc.contributor.author	Tann, Annabelle
dc.date.accessioned	2019-01-22T16:43:32Z
dc.date.available	2019-01-30T23:50:06Z
dc.date.issued	2019-01-22
dc.identifier.uri	http://hdl.handle.net/11858/00-1735-0000-002E-E564-A
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-7241
dc.language.iso	deu	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc	610	de
dc.title	Bedeutung genetischer Polymorphismen im organischen Kationentransporter OCT1 für die Pharmakokinetik und Nebenwirkungen von Proguanil	de
dc.type	doctoralThesis	de
dc.title.translated	Impact of genetic polymorphisms in organic cation transporter OCT1 on pharmacokinetics and side effects of Proguanil	de
dc.contributor.referee	Brockmöller, Jürgen Prof. Dr.
dc.date.examination	2019-01-23
dc.description.abstracteng	Currently, only limited data exists regarding organic cation transporter OCT1 in the context of polymorphisms in drug transporters and their impact on pharmacokinetics of drugs in humans. In vitro experiments showed that the antimalarial drug proguanil and its active metabolite cycloguanil are substrates of OCT1. Polymorphisms in OCT1 had a significant influence on proguanil uptake into the liver. Suppression of OCT1 led to reduced uptake of proguanil and an impaired bioactivation to cycloguanil. However, there was no existing data on genetic polymorphisms in OCT1 and their impact on pharmacokinetics of proguanil in vivo. This is why we conducted a clinical trial where we administered 200 mg proguanil per os to 39 healthy subjects. Blood samples were collected up to 36 hours after administration and pharmacokinetic parameters in blood and plasma were calculated. OCT1 deficiency led to significantly lower concentrations of cycloguanil in blood. This is caused by OCT1 deficiency, which leads to impaired proguanil uptake into the liver and therefore impaired bioactivation to cycloguanil. This step might influence the efficacy of proguanil, which this trial could not yet prove. There was no influence of polymorphisms in OCT1 on side effects of proguanil. On the other side, lower dose rates of cycloguanil resulting from OCT1 polymorphisms could favour the selection of resistant parasites in antimalarial therapy. In contrast to the results of in vitro experiments, OCT1 deficient subjects did not have much higher concentrations of proguanil in blood. This might be explained by the up to 50% renal elimination of proguanil and therefore only limited impact of hepatic clearance on concentrations of proguanil in blood. Furthermore, this trial did not include subjects with complete OCT1 deficiency. The concentration of proguanil in blood was threefold higher than in plasma, which suggested the active uptake of proguanil in erythrocytes. However, there was no significant influence of OCT1 on this uptake. In this trial, we confirmed the known impact of polymorphisms in CYP2C19 on proguanil pharmacokinetics. Concerning drug interactions, the intake of oral contraceptives had no significant impact on CYP2C19 regarding proguanil concentrations in blood. Furthermore, CYP3A5-deficient subjects had a higher ratio of cycloguail over proguanil in blood than subjects without impaired enzymatic function. This might suggest either that CYP3A5 plays a role in further metabolism of cycloguanil, or that CYP3A5 has relevance for the formation of inactive metabolite chlorphenylbiguanide. In conclusion, this trial confirmed for the first time the influence of OCT1 deficiency on bioactivation from proguanil to cycloguanil in humans and, therefore, on the concentrations of cycloguanil in blood. Together with polymorphisms in liver enzymes CYP2C19 and CYP3A5, 34% of variation in concentrations of cycloguanil in blood could be explained. Further clinical trials would be required to confirm consequences of these findings for efficacy and side effects in the antimalarial therapy with proguanil.	de
dc.contributor.coReferee	Hahn, Heidi Prof. Dr.
dc.subject.ger	genetischer Polymorphismus	de
dc.subject.ger	Proguanil	de
dc.subject.ger	Cycloguanil	de
dc.subject.ger	Pharmakokinetik	de
dc.subject.ger	Membrantransport	de
dc.subject.ger	OCT1	de
dc.subject.ger	Organischer Kationentransporter OCT1	de
dc.subject.eng	organic cation transporter OCT1	de
dc.subject.eng	genetic polymorphism	de
dc.subject.eng	proguanil	de
dc.subject.eng	cycloguanil	de
dc.subject.eng	pharmacokinetics	de
dc.identifier.urn	urn:nbn:de:gbv:7-11858/00-1735-0000-002E-E564-A-2
dc.affiliation.institute	Medizinische Fakultät	de
dc.subject.gokfull	GOK-MEDIZIN	de
dc.description.embargoed	2019-01-30
dc.identifier.ppn	104718480X

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