FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W919562823> ?p ?o ?g. }

• W919562823 abstract "Propafenone is a class 1C antiarrhythmic drug used for the treatment of ventricular arrhythmias. Propafenone is a chiral compound which is normally administered as the racemate. The use of racemate therapy can be problematic as variability in both the pharmacodynamic and pharmacokinetic properties of the separate enantiomeric forms of the drug can exist. Propafenone enantiomers have been shown to have similar pharmacological properties, but studies are limited with regards to their disposition and interaction with drug metabolising enzymes. The aim of the study conducted here was to investigate the interaction of racaemic propafenone with the major cytochrome P450 isoforms (CYP2D6, CYP1A2, CYP3A4 and CYP2C19) to determine any stereospecific differences which may exist. This was conducted by measuring the in vitro metabolism of propafenone (racemate and enatiomers) and by developing CYP inhibition screens which could prove to be useful in providing information of potential drug interactions. In addition, stereospecific binding to human albumin was measured to investigate whether any enantiomeric differences in unbound drug exist.For the inhibition studies propafenone (racemate and enatiomers) was incubated in 96 well plates with separate CYP isoforms in the presence of a NADPH regenerating system. CYP activity was monitored using the following fluorogenic substrates: CYP2C19/ CYP1A2 – CEC; CYP2D6 – AMMC; CYP3A4 - BFC. IC50 values were calculated and compared to those of control inhibitors (CYP2C19 – Tranycylpromine; CYP2D6 – Quinidine; CYP3A4 – Ketoconazole ; CYP1A2 - Furafylline). In vitro metabolism was conducted using human liver microsomes incubated with propafenone (racemate and enatiomers) and the degree of metabolism measured using hplc analysis. Protein binding was estimated for propafenone (racemate and enatiomers) by a chromatographic method utilising a chiral HSA column. Inhibition studies showed that the lowest IC50 values were obtained when propafenone was co-incubated with CYP2D6 and CYP 3A4 which is to be expected as these CYP isoforms have been shown previously to be the major ones responsible for phase 1 metabolism of racaemic propafenone. There was a distinct stereospecific difference with these isoforms, with the R-enantiomer showing a higher degree of inhibition. This would suggest that there may be merit in considering single enantiomer therapy (in this instance using the S-enantiomer) to minimise the risk of any drug-drug interactions in vivo. However, the in vitro metabolism study showed that both single enantiomers were metabolised at a higher rate than the racaemic mixture. This may be explained in terms of the 2 enantiomers competing for metabolism and thus inhibiting the metabolism of each other. These results suggest a possible problem with single enantiomer therapy of propafenone as this drug has a short half life and increased metabolism would decrease this even further. Investigations into the plasma protein binding of propafenone showed that there is no difference in the binding of the separate enantiomers and therefore there would be no stereospecific differences in free drug concentration, although propafenone also binds to acid glycoprotein and so binding studies with separate enantiomers need to be conducted with this protein too.Overall, this study shows how in vitro techniques can be utilised to investigate stereospecific differences in drug disposition. The work described here warrants further study on the metabolism/disposition of propafenone enantiomers in vivo to examine the clinical implications of enantiospecific therapy with this drug." @default.
• W919562823 created "2016-06-24" @default.
• W919562823 creator A5088762322 @default.
• W919562823 date "2010-08-17" @default.
• W919562823 modified "2023-09-26" @default.
• W919562823 title "The interactions of Propafenone and its enantiomers with the major human forms of cytochrome P450 in terms of inhibition and metabolic rates" @default.
• W919562823 cites W1527699425 @default.
• W919562823 cites W1549817255 @default.
• W919562823 cites W1553828925 @default.
• W919562823 cites W157413753 @default.
• W919562823 cites W1575242129 @default.
• W919562823 cites W1582717560 @default.
• W919562823 cites W1592112313 @default.
• W919562823 cites W1900740515 @default.
• W919562823 cites W1966050415 @default.
• W919562823 cites W1970748903 @default.
• W919562823 cites W1979259734 @default.
• W919562823 cites W1984926273 @default.
• W919562823 cites W1987513913 @default.
• W919562823 cites W1987525830 @default.
• W919562823 cites W1994438706 @default.
• W919562823 cites W1995496266 @default.
• W919562823 cites W1995929640 @default.
• W919562823 cites W1999463082 @default.
• W919562823 cites W2003678776 @default.
• W919562823 cites W2006962926 @default.
• W919562823 cites W2025329213 @default.
• W919562823 cites W2026330543 @default.
• W919562823 cites W2027647983 @default.
• W919562823 cites W2028083167 @default.
• W919562823 cites W2038208755 @default.
• W919562823 cites W2038239803 @default.
• W919562823 cites W2049271629 @default.
• W919562823 cites W2052321618 @default.
• W919562823 cites W2062117607 @default.
• W919562823 cites W2072266916 @default.
• W919562823 cites W2080126574 @default.
• W919562823 cites W2096523795 @default.
• W919562823 cites W2105624923 @default.
• W919562823 cites W2132927623 @default.
• W919562823 cites W2133270655 @default.
• W919562823 cites W2137442330 @default.
• W919562823 cites W2143812900 @default.
• W919562823 cites W2147549002 @default.
• W919562823 cites W2153126387 @default.
• W919562823 cites W2315156244 @default.
• W919562823 cites W2322128527 @default.
• W919562823 cites W2332494492 @default.
• W919562823 cites W2348657750 @default.
• W919562823 cites W2414294409 @default.
• W919562823 cites W2418077170 @default.
• W919562823 cites W2437691592 @default.
• W919562823 cites W2487290879 @default.
• W919562823 cites W3126152828 @default.
• W919562823 cites W3195431600 @default.
• W919562823 cites W635150764 @default.
• W919562823 cites W636519060 @default.
• W919562823 cites W1997421891 @default.
• W919562823 cites W2002613537 @default.
• W919562823 cites W2798519167 @default.
• W919562823 hasPublicationYear "2010" @default.
• W919562823 type Work @default.
• W919562823 sameAs 919562823 @default.
• W919562823 citedByCount "0" @default.
• W919562823 crossrefType "dissertation" @default.
• W919562823 hasAuthorship W919562823A5088762322 @default.
• W919562823 hasConcept C109650736 @default.
• W919562823 hasConcept C112705442 @default.
• W919562823 hasConcept C126322002 @default.
• W919562823 hasConcept C140840227 @default.
• W919562823 hasConcept C185592680 @default.
• W919562823 hasConcept C202751555 @default.
• W919562823 hasConcept C2779161974 @default.
• W919562823 hasConcept C2780035454 @default.
• W919562823 hasConcept C2780339425 @default.
• W919562823 hasConcept C2781472538 @default.
• W919562823 hasConcept C33664856 @default.
• W919562823 hasConcept C486523 @default.
• W919562823 hasConcept C526171541 @default.
• W919562823 hasConcept C55493867 @default.
• W919562823 hasConcept C62231903 @default.
• W919562823 hasConcept C71240020 @default.
• W919562823 hasConcept C71924100 @default.
• W919562823 hasConcept C86745063 @default.
• W919562823 hasConcept C87644729 @default.
• W919562823 hasConcept C89311334 @default.
• W919562823 hasConcept C97320921 @default.
• W919562823 hasConcept C98274493 @default.
• W919562823 hasConceptScore W919562823C109650736 @default.
• W919562823 hasConceptScore W919562823C112705442 @default.
• W919562823 hasConceptScore W919562823C126322002 @default.
• W919562823 hasConceptScore W919562823C140840227 @default.
• W919562823 hasConceptScore W919562823C185592680 @default.
• W919562823 hasConceptScore W919562823C202751555 @default.
• W919562823 hasConceptScore W919562823C2779161974 @default.
• W919562823 hasConceptScore W919562823C2780035454 @default.
• W919562823 hasConceptScore W919562823C2780339425 @default.
• W919562823 hasConceptScore W919562823C2781472538 @default.
• W919562823 hasConceptScore W919562823C33664856 @default.
• W919562823 hasConceptScore W919562823C486523 @default.

• next