title: Effects of Cremophor EL on the absorption of orally administered saquinavir and fexofenadine in healthy subjects.
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.
authors.affiliation: Department of Pharmaceutics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Tomaru
authors.affiliation: Department of Pharmaceutics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan; Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo, 650-8586, Japan. Electronic address: mmtakeda@pharm.kobegakuin.ac.jp.
authors.forename: Mariko
authors.initials: M
authors.lastname: Takeda-Morishita
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Department of Pharmaceutics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Banba
authors.affiliation: Department of Pharmaceutics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Takayama
authors.affiliation: Clinical Trial Center, Kitasato East Hospital, 2-1-1 Azamizodai, Minami-ku, Sagamihara, Kanagawa, 252-0380, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kumagai
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan; Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Research Cluster for Innovation, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D065567:Absorption, Physiological; D000284:Administration, Oral; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005079:Excipients / Q000737:chemistry / Q000494:pharmacology*; D005990:Glycerol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D019258:Saquinavir / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry; D013379:Substrate Specificity; D016593:Terfenadine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005079:Excipients; C000515:cremophor EL; D016593:Terfenadine; C093230:fexofenadine; D051544:Cytochrome P-450 CYP3A; D019258:Saquinavir; D005990:Glycerol
keywords: Cremophor EL; Fexofenadine; Oral absorption; P-gp; Saquinavir