Pharmacokinetics of the CYP 3A substrate simvastatin following administration of delayed versus immediate release oral dosage forms.
OBJECTIVE
The study was designed to evaluate the effect of delayed release (DR) on absorption and bioavailability of intestinally metabolized drugs after oral dosing, using the HMG-CoA reductase inhibitor simvastatin, a CYP3A substrate, as a model drug.


METHODS
To target drug release and to assess regional gastrointestinal absorption of the CYP 3A substrate simvastatin from the distal parts of the intestine, delayed release film coated tableted oral dosage forms were developed. Simvastatin delayed release tablet, simvastatin immediate release capsule and simvastatin immediate release tablet Zocor were administered as single doses (20 mg) to fasting healthy volunteers in a crossover design.


RESULTS
Simvastatin bioavailability was increased by a factor of three, as compared to the reference formulation Zocor. The overall metabolite levels from the immediate release capsules tended to be higher throughout the period studied than the metabolite levels following administration of Zocor and simvastatin delayed release dosage form.


CONCLUSIONS
The interplay between gastrointestinal physiology (lower CYP 3A expression in the distal ileum and the colon) and formulation design (zero-order controlled release after a predetermined lag-time) resulted in successful absorption and bioavailability improvement and represent a viable strategy to reduce the dose of CYP 3A drugs.
Tubic-Grozdanis
Marija
M
Department of Pharmaceutical Technology and Biopharmaceutics, Johannes Gutenberg-University, Staudinger Weg 5, 55099 Mainz, Germany.
Hilfinger
John M
JM
Amidon
Gordon L
GL
Kim
Jae Seung
JS
Kijek
Paul
P
Staubach
Petra
P
Langguth
Peter
P
D000180:Acrylic Resins; D000328:Adult; D000465:Algorithms; D019540:Area Under Curve; D001682:Biological Availability; D002214:Capsules; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003692:Delayed-Action Preparations; D005079:Excipients; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D008297:Male; D019821:Simvastatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet
D000180:Acrylic Resins; D002214:Capsules; D003692:Delayed-Action Preparations; D005079:Excipients; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C050528:Eudragit RS; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A