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THE EFFECT OF MULTIPLE-DOSE PAROXETINE ON THE PHARMACOKINETIC PROFILE OF CARVEDILOL IN RATS

100%

Abrudan M. B., Muntean D. M., Neag M. A., Vlase L., Gheldiu A. M.

Acta Poloniae Pharmaceutica - Drug Research

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2018

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vol. 75

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issue 5

1241-1246

EN

The aim of the present study was to evaluate the effect of multiple-dose paroxetine upon the pharmacokinetic profile of carvedilol in rats. Carvedilol was orally administrated in rats (3.57 mg/kg body mass (b.m.)) in the absence of paroxetine or after a pre-treatment with multiple oral doses of paroxetine (7.14 mg/kg b.m.). The plasma concentrations of carvedilol were estimated by high performance liquid chromatography-tandem mass spectrometry. After carvediol co-administration with paroxetine, an approximately 4.5-fold increase in the exposure of carvedilol was observed, considering the significantly elevated value of AUC0-∞. Furthermore, an increase by 72% of peak plasma concentration was found, as well as an augmentation by 91% of the half life time of carvedilol was observed. Paroxetine co-administration led to a significant alteration of carvedilol’s pharmacokinetic profile in rats, these effects could be explained by the existence of a drug-drug interaction mediated by CYP2D6 inhibition.

2

In Vitro approach for identification of a leading cytochrome P450 isoenzyme responsible for biotransformation of novel arylpiperazine drug candidates and their inhibition potency towards CYP3A4.

86%

Ulenberg S., Belka M., Georgiev P., Król M., Herold F., Bączek T.

Acta Poloniae Pharmaceutica - Drug Research

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2020

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vol. 77

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issue 1

69-76

EN

Presented article is a follow-up study of previous work, published in PLoS ONE in 2015 regarding metabolic stability of arylpiperazine derivatives, a very promising group of novel antidepressants. The aim of this study was to identify cytochrome P450 (CYP) isoforms that participate in the metabolism of some novel arylpiperazine derivatives developed by authors as well as their potency to inhibit reactions catalysed by identified lead metabolizing enzyme. Such studies allow to predict possible drug-drug interactions that might occur during co-administration of studied compounds with other drugs that are metabolized by identified enzyme. The compounds were incubated in vitro together with the isolated CYP isoforms. After the incubation, samples were analyzed by liquid chromatography coupled with mass spectrometry. The results showed main contribution of CYP3A4 isoform in biotransformation of the investigated derivatives. With CYP3A4 being the main CYP isoform responsible for the metabolism of arylpiperazine derivatives and at the same time being the main metabolizing enzyme for almost 50% of all drugs, a high chance of in vivo drug-drug interactions emerged. Therefore, IC50 values were also determined using testosterone hydroxylation as a probe reaction, specific for CYP3A4. The resulting values ranged from 6.13 to 15.85 µM, which places studied derivatives as moderate or weak inhibitors of CYP3A4. Those results, combined with conclusion that all of the arylpiperazine derivatives are also metabolized to some extent by other CYP isoforms (providing alternative metabolic pathways), result in conclusion that studied arylpiperazines might be safe for co-administration with other CYP3A4 substrates.

3

Monooksygenazy zależne od cytochromu P-450 oraz enzymy II fazy przemian ksenobiotykow w łożysku

72%

Włoch S.

Annales Academiae Medicae Silesiensis

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2009

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vol. 63

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issue 2

78-84

EN

The fi rst part of this paper contains the discussion of the organization of the basic P-450 cytochrome-dependent monooxygenases including the functional diff erences resulting from their location in the microsomal and mitochondrial fractions, the basic stages of the pertinent metabolic changes, and also, the mechanisms of induction of the Cyp.-450 in the families 1,2,3 and 4. In the next part, the current state of knowledge on monooxygenases in the placental cells has been presented. Attention has been drawn to the fact that despite the low contents of both mRNA and CYP-450 protein in the families 1,2,3 and 4 in syncytiotrophoblast cells at the level of just several percent hepatocytes, this system may perform an important role in the release of indirect toxic metabolites , thus posing threat to the lives of either the embryo or the fetus, particularly in the fi rst trimester of pregnancy. These risks substantially increase in situations where the pregnant woman has had contact with medicines, alcohol, narcotics or tobacco smoke, which are found to be eff ective CYP-450 inducers or inhibitors. In the fi nal part, the activity of Phase II xenobiotic metabolism enzymes in the placenta has been discussed, including UDP-gluconylotransferase, 5-glutation transferase, and sulfotransferases.

PL

W części pierwszej omówiono organizację podstawowych ogniw monooksygenaz zależnych od cytochromu P-450, różnice funkcjonalne wynikające z ich posadowienia we frakcji mikrosomalnej i mitochondrialnej komórek, podstawowe etapy realizowanych przemian, a także mechanizmy indukcji rodziny 1,2,3 i 4 CYP.-450. Następnie przedstawiono aktualny stan wiedzy na temat monooksygenaz w komórkach łożyska. Zwrócono uwagę, iż pomimo niskich zawartości mRNA i białka CYP-450 rodziny 1,2 oraz 3 w komórkach syncytiotrofoblastu na poziomie zaledwie kilkuprocentowym hepatocytów, układ ten może spełniać ważną rolę w uwalnianiu toksycznych metabolitów pośrednich, stwarzając zagrożenie dla zdrowia i rozwoju zarodka oraz płodu, zwłaszcza w I trymestrze ciąży. Owe zagrożenia zdecydowanie wzrastają w warunkach kontaktu ciężarnej kobiety z lekami, dymem papierosowym, alkoholem, narkotykami, które są efektywnymi induktorami lub inhibitorami CYP-450. Omówiono także aktywność w łożysku enzymów II fazy przemian ksenobiotyków, w tym: UDP-glukonylotransferazy, transferazy S-glutationowej i sufotransferaz.

4

Polimorfi zm genetyczny wybranych alleli cytochromu CYP2D6 u pacjentów z kardiomiopatią rozstrzeniową i zapaleniem mięśnia sercowego

72%

Smolik S., Domal-Kwiatkowska D., Węglarz L.

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EN

Cytochrome P450 2D6 has been reported to possess variation in the encoding gene that aff ects enzymatic activity. Interindividual diff erences in CYP2D6 activity can produce adverse eff ects or lack of therapeutic eff ect under standard therapy. The aim of the study was to genotyope the chosen alleles of CYP2D6 among the patients with clinically confi rmed myocarditis or dilated cardiomyopathy. Tetra-primer PCR assays was used to detect mutations in CYP2D6 *3, *4 and *6 allelles among 53 patients. A multiplex long PCR was used to genotype CYP2D6*5 allele. Analysis showed the presence of one heterozygote for CYP2D6*3, two heterozygote for CYP2D6*6, ten heterozygote and two homozygote for CYP2D6*4 among the examined patients. One person with deletion of CYP2D6 locus was also detected. Presented methods will facilitate and accelerate the detailed pharmacogenomic analysis of CYP2D6.

PL

Cytochrom CYP2D6 ma różne warianty sekwencji kodującego go genu, wpływające na jego aktywność enzymatyczną. Międzyosobnicze różnice w aktywności izoenzymu CYP2D6 mogą prowadzić do działań niepożądanych lub braku skuteczności terapeutycznej standardowych dawek leku. Celem pracy było genotypowanie wybranych alleli CYP2D6 w grupie pacjentów z potwierdzonym klinicznie stanem zapalnym mięśnia sercowego lub kardiomiopatią rozstrzeniową. W pracy zastosowano reakcję PCR z użyciem czterech starterów w celu detekcji alleli 3*,4* i 6* CYP2D6 w grupie 53 pacjentów. Do wykrycia allelu CY2D6*5 zastosowano długołańcuchową reakcję PCR typu multipleks. Przeprowadzona analiza wykazała w badanej grupie pacjentów obecność jednej heterozygoty dla allelu CYP2D6*3, dwóch heterozygot dla allelu CYP2D*6, dziesięciu heterozygot i dwóch homozygot dla alellu CYP2D6*4. Znaleziono także jedną osobę z delecją locus CYP2D6. Przedstawione metody ułatwiają i przyspieszają dokładną analizę farmakogenetyczną izoformy CYP2D6.

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2 Acta Poloniae Pharmaceutica - Drug Research

2 Annales Academiae Medicae Silesiensis

1 2020

1 2018

1 2011

1 2009

1 Abrudan M. B.

1 Belka M.

1 Bączek T.

1 Domal-Kwiatkowska D.

1 Georgiev P.

1 Gheldiu A. M.

1 Herold F.

1 Król M.

1 Muntean D. M.

1 Neag M. A.

1 Smolik S.

1 Ulenberg S.

1 Vlase L.

1 Węglarz L.

1 Włoch S.

THE EFFECT OF MULTIPLE-DOSE PAROXETINE ON THE PHARMACOKINETIC PROFILE OF CARVEDILOL IN RATS

In Vitro approach for identification of a leading cytochrome P450 isoenzyme responsible for biotransformation of novel arylpiperazine drug candidates and their inhibition potency towards CYP3A4.

Monooksygenazy zależne od cytochromu P-450 oraz enzymy II fazy przemian ksenobiotykow w łożysku

Polimorfi zm genetyczny wybranych alleli cytochromu CYP2D6 u pacjentów z kardiomiopatią rozstrzeniową i zapaleniem mięśnia sercowego