Dataset Information

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.

SUBMITTER: Yago MR

PROVIDER: S-EPMC4389759 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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The use of betaine HCl to enhance dasatinib absorption in healthy volunteers with rabeprazole-induced hypochlorhydria.

Yago Marc R MR Frymoyer Adam A Benet Leslie Z LZ Smelick Gillian S GS Frassetto Lynda A LA Ding Xiao X Dean Brian B Salphati Laurent L Budha Nageshwar N Jin Jin Y JY Dresser Mark J MJ Ware Joseph A JA

The AAPS journal 20141002 6

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 ...[more]

PMID: 25274610

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Project description:ObjectivesWe investigated whether lowering of fasting homocysteine concentrations, either with folic acid or with betaine supplementation, differentially affects vascular function, a surrogate marker for risk of cardiovascular disease, in healthy volunteers. As yet, it remains uncertain whether a high concentration of homocysteine itself or whether a low folate status--its main determinant--is involved in the pathogenesis of cardiovascular disease. To shed light on this issue, we performed this study.DesignThis was a randomized, placebo-controlled, double-blind, crossover study.SettingThe study was performed at Wageningen University in Wageningen, the Netherlands.ParticipantsParticipants were 39 apparently healthy men and women, aged 50-70 y.InterventionsParticipants ingested 0.8 mg/d of folic acid, 6 g/d of betaine, and placebo for 6 wk each, with 6-wk washout in between.Outcome measuresAt the end of each supplementation period, plasma homocysteine concentrations and flow-mediated dilation (FMD) of the brachial artery were measured in duplicate.ResultsFolic acid supplementation lowered fasting homocysteine by 20% (-2.0 micromol/l, 95% confidence interval [CI]: -2.3; -1.6), and betaine supplementation lowered fasting plasma homocysteine by 12% (-1.2 micromol/l; -1.6; -0.8) relative to placebo. Mean (+/- SD) FMD after placebo supplementation was 2.8 (+/- 1.8) FMD%. Supplementation with betaine or folic acid did not affect FMD relative to placebo; differences relative to placebo were -0.4 FMD% (95%CI, -1.2; 0.4) and -0.1 FMD% (-0.9; 0.7), respectively.ConclusionsFolic acid and betaine supplementation both did not improve vascular function in healthy volunteers, despite evident homocysteine lowering. This is in agreement with other studies in healthy participants, the majority of which also fail to find improved vascular function upon folic acid treatment. However, homocysteine or folate might of course affect cardiovascular disease risk through other mechanisms.

Project description:INTRODUCTION:The menisci are responsible for several functions. They are shock absorbers during dynamic loading on the knee and provide a broader surface area on which to distribute stress evenly to the tibia and femur. These functions allow for smoother movement and greater stability of the knee joint. Meniscal injury can be a great impediment to the function of the knee. Therefore, in the case of meniscal injury, our main concern is the relief of patient symptoms, followed by consequent restoration of meniscal function to the greatest of our ability. To prevent the long terms effects of a meniscectomy, meniscal allograft transplantation (MAT) was developed. The potential of using the size of the contralateral healthy menisci, to determine the size of the menisci to be replaced, will be discussed. METHODS:Knee MRIs done on healthy patients in the past 5 years were reviewed. Magnetic Resonance Imaging was performed using a 3-T scanner. Each individual was examined with knee joints in full extension. Measurements were performed two separate times, two weeks apart. A mean of three measurements was made during each session to reduce error. Thirty-eight normal bilateral knee joints MRIs remained (16 males, 22 females). Participants were sampled from the institutional Picture Archiving and Communication System (PACS). Age, gender, and the medial meniscal and lateral meniscal size of both knees were recorded. The laterality of the menisci was compared between both knees in each patient. RESULTS:A total of 38 patients were included in this study, with a mean age of 37.39 (±9.50) years. They were 16 (42.1%) men and 22 (57.9%) women. We didn't find any significant difference in the mid-coronal section between left and right knees meniscal measurements. None of the measurements were significantly different between men and women. There was no significant difference in the medial mid-sagittal section or lateral mid-sagittal section between left and right knee meniscal measurements. CONCLUSION:The results obtained in this study may support the use of MRI of the bilateral knee to obtain an appropriately sized allograft.

Dataset Information

The use of betaine HCl to enhance dasatinib absorption in healthy volunteers with rabeprazole-induced hypochlorhydria.

Publications

The use of betaine HCl to enhance dasatinib absorption in healthy volunteers with rabeprazole-induced hypochlorhydria.

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