Cerivastatin in vitro metabolism by CYP2C8 variants found in patients experiencing rhabdomyolysis.
OBJECTIVE
Cerivastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor withdrawn from the market because of serious adverse effects, is metabolized primarily by CYP2C8. The occurrence of associated myotoxicity and rhabdomyolysis were attributed to altered cerivastatin pharmacokinetics on account of gemfibrozil-inhibition or genetic variations in CYP2C8 and drug transporters involved in cerivastatin clearance. However, the effect of CYP2C8 genetic variation on cerivastatin metabolism has not been fully elucidated.


METHODS
In this study, patients (n=126) with confirmed cases of rhabdomyolysis after cerivastatin administration had their CYP2C8 gene resequenced and the metabolism of cerivastatin by the discovered CYP2C8 variants was assessed in proteins expressed in Escherichia coli.


RESULTS
In this unique patient population, 12 novel single nucleotide polymorphisms were discovered of which six were exclusively found in patients not using gemfibrozil. Three rare exonic variants resulted in amino acid substitutions and a frame shift deletion (V472fsL494 generating a defective mostly heme-free CYP2C8 protein). A particular promoter located deletion (-635_-634delTA) was tightly linked to CYP2C8*3. Heterologously expressed CYP2C8.3 and CYP2C8.4 displayed an increase in cerivastatin metabolic clearance of up to six-fold compared with the wild-type enzyme. Similarly, an independent sample of microsomes from human livers carrying the CYP2C8*3 and CYP2C8*4 alleles exhibited a 2-fold to 14-fold increase in normalized cerivastatin intrinsic clearance, compared with microsomes from livers carrying only the wild type allele.


CONCLUSIONS
Gain or loss of catalytic function found in the CYP2C8 gene could certainly alter cerivastatin pharmacokinetics and may influence, at least in part, susceptibility to the development of myotoxicity.
Kaspera
Rüdiger
R
Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195-7610, USA.
Naraharisetti
Suresh B
SB
Tamraz
Bani
B
Sahele
Tariku
T
Cheesman
Matthew J
MJ
Kwok
Pui-Yan
PY
Marciante
Kristin
K
Heckbert
Susan R
SR
Psaty
Bruce M
BM
Totah
Rheem A
RA
D000483:Alleles; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D055162:Biocatalysis; D018360:Crystallography, X-Ray; D065727:Cytochrome P-450 CYP2C8; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008862:Microsomes, Liver / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011725:Pyridines / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012206:Rhabdomyolysis / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics*; D017422:Sequence Analysis, DNA
D011725:Pyridines; D011994:Recombinant Proteins; C086276:cerivastatin; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8