Question

Case Study 1
A 75-year-old man presented to the hospital with symptoms of muscle weakness, stiffness, and dark urine. A diagnosis of rhabdomyolysis and acute renal failure was made. The patient’s medical history included hypercholesteremia for which he took atorvastatin for approximately 2 years. Verapamil treatment had recently been initiated for hypertension. Upon admission, all medications were discontinued, and the patient was treated with intermittent hemodialysis. Genotyping results showed that the patient had a single-nucleotide polymorphism (SNP) within genes encoding the organic anion-transporting polypeptide (OATP) 1B1. He was also found to be a poor metabolizer of CYP2C19.

A. Discuss the causes of the patient’s symptoms, including the type of interaction between atorvastatin and verapamil and the effect of the SNP.

Answer 1

Atorvastatin is metabolized extensively by CYP3A4 in the liver, and verapamil is a moderate inhibitor of CYP3A4. Initiation of verapamil therapy led to inhibition of CYP3A4 metabolism, which is believed to have contributed to atorvastatin overexposure, thus increasing the risk of rhabdomyolysis.

Atorvastatin is also a substrate for OATP1B1 hepatic uptake transporter. Therefore, the patient’s SNP in OATP1B1 may have contributed to the adverse event by decreasing the hepatic uptake of atorvastatin, thereby increasing the circulating levels of atorvastatin.

This case illustrates the clinical relevance and relationship between pharmacogenetics and drug-drug interactions in the development of statin-induced myopathy.