Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use

Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use

Sebastian J. Padayatty, MRCP, PhD;
He Sun, PhD, CBS;
Yaohui Wang, MD;
Hugh D. Riordan, MD;
Stephen M. Hewitt, MD, PhD;
Arie Katz, MD;
Robert A. Wesley, PhD; and
Mark Levine, MD

From the National Institute of Diabetes and Digestive and Kidney Diseases, the National Cancer Institute, and the Clinical Center, National Institutes of Health, Bethesda, Maryland; the Food and Drug Administration, Rockville, Maryland; and Bio-Communications Research Institute, Wichita, Kansas.

Abstract

Background: Vitamin C at high concentrations is toxic to cancer cells in vitro. Early clinical studies of vitamin C in patients with terminal cancer suggested clinical benefit, but 2 double-blind, placebo-controlled trials showed none. However, these studies used different routes of administration.

Objective: To determine whether plasma vitamin C concentrations vary substantially with the route of administration.

Design: Dose concentration studies and pharmacokinetic modeling.

Setting: Academic medical center.

Participants: 17 healthy hospitalized volunteers.

Measurements: Vitamin C plasma and urine concentrations were measured after administration of oral and intravenous doses at a dose range of 0.015 to 1.25 g, and plasma concentrations were calculated for a dose range of 1 to 100 g.

Results: Peak plasma vitamin C concentrations were higher after administration of intravenous doses than after administration of oral doses (P < 0.001), and the difference increased according to dose. Vitamin C at a dose of 1.25 g administered orally produced mean (±sd) peak plasma concentrations of 134.8 ± 20.6 µmol/L compared with 885 ± 201.2 µmol/L for intravenous administration. For the maximum tolerated oral dose of 3 g every 4 hours, pharmacokinetic modeling predicted peak plasma vitamin C concentrations of 220 µmol/L and 13 400 µmol/L for a 50-g intravenous dose. Peak predicted urine concentrations of vitamin C from intravenous administration were 140-fold higher than those from maximum oral doses.

Limitations: Patient data are not available to confirm pharmacokinetic modeling at high doses and in patients with cancer.

Conclusions: Oral vitamin C produces plasma concentrations that are tightly controlled. Only intravenous administration of vitamin C produces high plasma and urine concentrations that might have antitumor activity. Because efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated.

Article and Author Information

Grant Support: By a grant from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (Z01 DK 54506). Dr. Katz received partial support from the Office of Dietary Supplements, Office of the Director, National Institutes of Health.
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Mark Levine, MD, Molecular and Clinical Nutrition Section, Building 10, Room 4D52-MSC 1372, National Institutes of Health, Bethesda, MD 20892-1372.
Current Author Addresses: Dr. Padayatty, Wang, and Levine: Molecular and Clinical Nutrition Section, Building 10, Room 4D52-MSC 1372, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892-1372.
Dr. Sun: Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
Dr. Riordan: Bio-Communications Institute, 3100 North Hillside Avenue, Wichita, KS 67219.
Dr. Hewitt: National Cancer Institute, ATC 225D, MSC 4605, National Institutes of Health, Bethesda, MD 20802-4605.
Dr. Katz: Molecular and Clinical Nutrition Section, Building 10, Room 6C432B, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892.
Dr. Wesley: Clinical Center, Building 10, Room 10S246-MSC 1871, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 10892.
Author Contributions: Conception and design: S.J. Padayatty, H. Sun, Y. Wang, H.D. Riordan, S.M. Hewitt, M. Levine.
Analysis and interpretation of the data: S.J. Padayatty, H. Sun, Y. Wang, A. Katz, R.A. Wesley, M. Levine.
Drafting of the article: S.J. Padayatty, A. Katz, M. Levine.
Critical revision of the article for important intellectual content: S.J. Padayatty, H. Sun, Y. Wang, H.D. Riordan, S.M. Hewitt, A. Katz, M. Levine.
Final approval of the article: S.J. Padayatty, H. Sun, Y. Wang, H.D. Riordan, S.M. Hewitt, A. Katz, M. Levine.
Provision of study materials or patients: H.D. Riordan, M. Levine.
Statistical expertise: R.A. Wesley.
Obtaining of funding: M. Levine.
Administrative, technical, or logistic support: Y. Wang, M. Levine.
Collection and assembly of data: S.J. Padayatty, H. Sun, Y. Wang, H.D. Riordan, A. Katz, M. Levine.