Question

1. In what part of a hepatocyte would a drug interaction involving CYP enzymes most likely occur?

A. Endoplasmic reticulum

B. Lysosomes

C. Golgi apparatus

D.Outer cell membrane

E. Nucleus membrane

2. Simvastatin is at higher risk of initiating rhabdomyolysis when co-administered with all except the following?

A. Anti-IL-6 therapy (tocilizumab)

B. Strong CYP3A4 inhibitors

C. Grapefruit juice

D. Mechanism-based CYP3A4 inhibitors

E. Hepatocyte OATP inhibitors

Answer 1

Q1. Correct option: (A) Endoplasmic Reticulum.

Reason: Cytochrome p450 is found primarily in protein-processing organelles such as Endoplasmic Reticulum. It is an enzyme with various isotypes with roles in oxidation reactions involving fat, steroids, and xenobiotic metabolism.

Q2. Correct option: (A) Anti-IL-6 therapy (tocilizumab)

Reason: Simvastatin is a statin drug that inhibits HMG-CoA reductase. These statins are metabolized by the cytochrome P40 variant called the CYP3A4 enzyme. Inhibition of CYP3A4 by both strong CYP3A4 inhibitors and mechanism-based CYP3A4 inhibitors causes the plasma concentration of statins to rise. Increased plasma statin then mediates rhabdomyolysis i.e. breakdown of skeletal muscle cells. OATP or organic anion transporter polypeptides are transport proteins responsible for importing drugs from the blood. Hence, inhibition of OATP by OATP inhibitors causes the statin molecules to remain in the blood stimulating rhabdomyolysis. Grapefruit juice too has been found to increase plasma simvastatin concentration and consequently increases the chance of rhabdomyolysis. The drug tocilizumab, on the other hand, causes increased expression of the enzyme CYP3A4, thereby helping in metabolizing simvastatin and in turn, lowering plasma simvastatin concentration and consequently lowering the risk of rhabdomyolysis.