title: The use of betaine HCl to enhance dasatinib absorption in healthy volunteers with rabeprazole-induced hypochlorhydria.
abstract: Many orally administered, small-molecule, targeted anticancer drugs, such as dasatinib, exhibit pH-dependent solubility and reduced drug exposure when given with acid-reducing agents. We previously demonstrated that betaine hydrochloride (BHCl) can transiently re-acidify gastric pH in healthy volunteers with drug-induced hypochlorhydria. In this randomized, single-dose, three-way crossover study, healthy volunteers received dasatinib (100 mg) alone, after pretreatment with rabeprazole, and with 1500 mg BHCl after rabeprazole pretreatment, to determine if BHCl can enhance dasatinib absorption in hypochlorhydric conditions. Rabeprazole (20 mg b.i.d.) significantly reduced dasatinib Cmax and AUC0-∞ by 92 and 78%, respectively. However, coadministration of BHCl significantly increased dasatinib Cmax and AUC0-∞ by 15- and 6.7-fold, restoring them to 105 and 121%, respectively, of the control (dasatinib alone). Therefore, BHCl reversed the impact of hypochlorhydria on dasatinib drug exposure and may be an effective strategy to mitigate potential drug-drug interactions for drugs that exhibit pH-dependent solubility and are administered orally under hypochlorhydric conditions.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, 533 Parnassus Avenue, Room U-68, San Francisco, California, 94143-0912, USA.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Yago
authors.forename: Adam
authors.initials: A
authors.lastname: Frymoyer
authors.forename: Leslie Z
authors.initials: LZ
authors.lastname: Benet
authors.forename: Gillian S
authors.initials: GS
authors.lastname: Smelick
authors.forename: Lynda A
authors.initials: LA
authors.lastname: Frassetto
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.forename: Brian
authors.initials: B
authors.lastname: Dean
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: Nageshwar
authors.initials: N
authors.lastname: Budha
authors.forename: Jin Y
authors.initials: JY
authors.lastname: Jin
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dresser
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ware
mesh_terms: D065567:Absorption, Physiological / Q000187:drug effects*; D000126:Achlorhydria / Q000139:chemically induced / Q000378:metabolism*; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001622:Betaine / Q000008:administration & dosage / Q000494:pharmacology*; D018592:Cross-Over Studies; D000069439:Dasatinib; D004347:Drug Interactions; D005260:Female; D005744:Gastric Acid / Q000737:chemistry; D064368:Healthy Volunteers; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008875:Middle Aged; D054328:Proton Pump Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D064750:Rabeprazole / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013844:Thiazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D054328:Proton Pump Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D064750:Rabeprazole; D001622:Betaine; D000069439:Dasatinib