esterol uptake is augmented. Thus, simvastatin also enhances clearance of LDL. Simvastatin decreases serum total cholesterol (serum total-C), LDL-cholesterol, VLDL, triglycerides (TG), and apolipoprotein B (Apo-B), while increasing HDL-C. Simvastatin is administered in the evening hours since there is evidence for diurnal variation in the hepatic synthesis of cholesterol. HMG-CoA reductase inhibitors have been reported to decrease endogenous CoQ10 serum concentrations; the clinical significance of these effects is unknown.
PHARMACOKINETICS
The combination of ezetimibe; simvastatin is administered orally. No clinically significant pharmacokinetic interactions have been noted when ezetimibe was co-administered with the HMG-CoA reductase inhibitors studied (e.g., simvastatin). Concomitant administration of ezetimibe has no significant effect on the bioavailability of these statins; the bioavailability of total ezetimibe is also unaffected. The ezetimibe; simvastatin product is bioequivalent to the drugs coadministered separately.
Ezetimibe: Following systemic absorption, ezetimibe is extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Ezetimibe and ezetimibe-glucuronide are highly bound (> 90%) to human plasma proteins. Following absorption, ezetimibe is rapidly metabolized by glucuronidation to ezetimibe-glucuronide in the small intestine and liver. Metabolism by oxidative metabolism is minimal. Ezetimibe lacks significant inhibitor or inducer effects on cytochrome P-450 isoenzymes. Ezetimibe co-administration has no significant effect on specific probe drugs known to be metabolized by cytochrome P-450 enzymes (CYP1A2, CYP2D6, CYP2C8/9 and CYP3A4 isoenzymes). In addition, cimetidine (a non-specific cytochrome P-450 inhibitor) has no effect on the bioavailability of ezetimibe or total ezetimibe. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10—20% and 80—90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from the plasma with a half-life (T½) of about 22 hours. Ezetimibe is enterohepatically recirculated, as evidenced by multiple peaks in its plasma concentrations. Following oral administration of radiolabeled ezetimibe, total ezetimibe (ezetimibe plus ezetimibe-glucuronide) accounts for approximately 93% of the total plasma radioactivity. After 48 hours, the plasma radioactivity is undetectable. Over a 10 day period, approximately 78% and 11% of the administered dose is recovered in the feces and urine, respectively. Ezetimibe is the major component recovered in the feces and accounts for 69% of the administered dose, while ezetimibe-glucuronide is the major component recovered in the urine and accounts for 9% of the administered dose.
Simvastatin: Simvastatin is an inactive prodrug. It is the methylated derivative of lovastatin and, like lovastatin, must be activated in the liver. Both simvastatin and the active metabolite are strongly bound to plasma proteins (95%). Simvastatin and lovastatin are lipophilic, while pravastatin is hydrophilic. Being lipophilic, simvastatin is taken up by cells other than hepatocytes and, unlike pravastatin, simvastatin penetrates the CNS. Sixty percent of an oral dose is excreted in the feces and 13% in the urine. The half-life (T½) of simvastatin i |
