Co-administration of Fluvastatin and CYP3A4 and CYP2C8 Inhibitors May Increase the Exposure to Fluvastatin in Carriers of CYP2C9 Genetic Variants

Abstract

Fluvastatin, which is one of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins), is primarily metabolized by CYP2C9 and to a lesser extent by CYP3A4 and CYP2C8. Predictions of drug-drug interactions (DDI) are important for the safety of combination therapies with statins, in particular drugs that are metabolized by CYP3A4. Little information is available regarding drug interactions with fluvastatin. Since CYP2C9 is a polymorphic enzyme, we investigated the effect of DDI via CYP2C9, CYP3A4, and CYP2C8 on fluvastatin pharmacokinetics by using a validated prediction method in relation to CYP2C9 variants. The predicted increases in the area under the concentration-time curve (AUC) ratios of fluvastatin in carriers with CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/*3, and CYP2C9*3/*3 versus that found in carriers with CYP2C9*1/*1 were 1.16, 1.35, 1.37, 1.65, and 2.06, respectively. Our in silico model predicted that administration of fluvastatin in conjunction with the potent inhibitors that completely inhibited CYP3A4 and CYP2C8 in carriers with the CYP2C9*3/*3 variant would cause a 3.23- and 2.60-fold increase in the AUC ratios, respectively, when compared to that for the carriers with the CYP2C9*1/*1 taking fluvastatin alone. We also predicted the effect of telmisartan when coadministered with fluvastatin. Our prediction results showed that the interaction between telmisartan and fluvastatin via CYP enzymes were negligible in clinical situations.

Impact of CYP2D6 Functional Allelic Variations on Phenoconversion and Drug–Drug Interactions

“…Moreover, theoretical discussion on the basis of the static mechanistic equation of DDI prediction and observed PK data from the present study show that the greater the CYP activity resulting from genetic polymorphism, the greater the impact of an inhibitor of this same CYP on the clearance of a victim drug, mainly cleared by the inhibited pathway, will be. In the case of a victim metabolized by multiple pathways, genetic polymorphism affecting the function of a major clearance pathway will increase the contribution of the alternative minor pathway and therefore results in significant DDI when an inhibitor of the minor pathway is given concomitantly …”

Potential Pharmacokinetic Interactions of Common Cardiovascular Drugs and Selected European and Latin American Herbal Medicines: A Scoping Review

“…Statins are metabolized by various cytochrome P450 (CYP) isoenzymes. For instance, atorvastatin [ 28 , 29 , 34 ], fluvastatin [ 30 ], and simvastatin [ 28 , 29 , 35 ] are all metabolized by CYP3A4. Atorvastatin is also metabolized by CYP3A5 [ 29 ].…”

“…Atorvastatin is also metabolized by CYP3A5 [ 29 ]. In the case of fluvastatin, other CYP enzymes involved in its metabolism are CYP2C8 [ 30 ] and CYP2C9 [ 28 , 29 , 30 , 31 ]. Simvastatin is metabolized by CYP2C8 and CYP3A5 [ 29 ].…”

Estudio de las variantes alélicas CYP2C9*2 y CYP2C9*3 en muestras de población mestiza peruana

“…El gen CYP2C9, situado en el brazo largo del cromosoma 10 en la región 24 (10q24) 4 , presenta alelos cuyas frecuencias difieren entre los grupos étnicos y dependen de la ubicación geográfica de una determinada población 5 . La enzima CYP2C9 (miembro del sistema oxidasa de función mixta, citocromo P450: EC 1.14.13.48) metaboliza, aproximadamente, el 15 % de los fármacos 1 y el gen que la codifica presenta más de 60 variantes genéticas 6 del tipo SNP 5 , algunas de las cuales forman parte de las seis variantes alélicas de importancia clínica.…”

“…En los caucásicos se ha reportado que los genotipos CYP2C9*1/*2 , CYP2C9*1/*3 12 , 13 y CYP2C9*2/*2 son responsables de los efectos secundarios de la fenitoína 12 - 14 ; en los individuos indios, el CYP2C9*3/*3 12 , 15 , en japoneses, los genotipos CYP2C9*1/*3 y CYP2C19*1/*3 12 , y en los afroamericanos están implicados los genotipos CYP2C9*6/*6 y CYP2C19*1/*1 12 . Además, el CYP2C9 metaboliza el clopidogrel 16 , 17 , la S-warfarina 11 , la fluvastatina 6 , la glibenclamida, el losartán, el irbesartán, el ibuprofeno, el lornoxicam y el diclofenaco 18 .…”