Effects of Cremophor EL on the absorption of orally administered saquinavir and fexofenadine in healthy subjects

Drug Metab Pharmacokinet. 2015 Jun;30(3):221-6. doi: 10.1016/j.dmpk.2015.01.002. Epub 2015 Jan 29.

Abstract

Modulation of CYP3A and/or P-gp function by several excipients has been reported. However, relatively few studies have investigated their effects in humans. Therefore, the aim of this clinical study was to clarify the effects of Cremophor EL on the inhibition of CYP3A and P-gp in the human small intestine. Eight healthy Japanese subjects received an oral dose of saquinavir (2 mg, substrate of P-gp/CYP3A) or fexofenadine (50 μg, substrate of P-gp) without or with Cremophor EL (720 mg and 1440 mg). Significant increases in Cmax (1.3-fold) and AUC0-24 (1.6-fold) were observed for fexofenadine when administered with 1440 mg of Cremophor EL. In contrast, a significant decrease was observed for saquinavir when administered with 720 mg of Cremophor EL. The equilibrium dialysis experiment was performed to investigate the micellar interaction between Cremophor EL and drugs. The equilibrium dialysis study showed that saquinavir was far extensively entrapped into the micelles. The reduced concentration of free saquinavir by entrapping in micelles was considered to cause the reduction of systemic exposure for saquinavir. In conclusion, this clinical study suggests that Cremophor EL at least inhibits P-gp in the human small intestine.

Keywords: Cremophor EL; Fexofenadine; Oral absorption; P-gp; Saquinavir.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • Absorption, Physiological
  • Administration, Oral
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A / metabolism*
  • Excipients / chemistry
  • Excipients / pharmacology*
  • Glycerol / analogs & derivatives*
  • Glycerol / chemistry
  • Glycerol / pharmacology
  • Healthy Volunteers
  • Humans
  • Male
  • Saquinavir / administration & dosage
  • Saquinavir / blood*
  • Saquinavir / chemistry
  • Substrate Specificity
  • Terfenadine / administration & dosage
  • Terfenadine / analogs & derivatives*
  • Terfenadine / blood
  • Terfenadine / chemistry

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Excipients
  • cremophor EL
  • Terfenadine
  • fexofenadine
  • Cytochrome P-450 CYP3A
  • Saquinavir
  • Glycerol