Effect of High-Dose Vitamin C on the Steady-State Pharmacokinetics of the Protease Inhibitor Indinavir in Healthy Volunteers

Douglas Slain, Pharm.D.; Jarrett R. Amsden, Pharm.D.; Rashida A. Khakoo, M.D.; Melanie A. Fisher, M.D., M.S.; David Lalka, Ph.D.; Gerry R. Hobbs, Ph.D.


Pharmacotherapy. 2005;25(2):165-170. 

In This Article

Abstract and Introduction

Study Objective: To determine whether daily high-dose vitamin C alters the steady-state pharmacokinetics of indinavir, a protease inhibitor indicated for treatment of the human immunodeficiency virus type 1.
Design: Prospective, open-label, longitudinal, two-period time series.
Setting: University medical center.
Subjects: Seven healthy volunteers.
Intervention: Indinavir 800 mg every 8 hours was given to subjects for four doses on days 1 and 2. Plasma samples were then collected for indinavir pharmacokinetic determination. After a 7-day washout period, subjects were given vitamin C 1000 mg/day for 7 days. Beginning on day 6 of vitamin C administration, indinavir 800 mg every 8 hours was restarted for four doses. Plasma was then collected from subjects to determine indinavir pharmacokinetics. All subjects were given a vitamin C content-controlled diet for 1 week before the study began and throughout the study period.
Measurements and Main Results: Steady-state plasma samples were collected before dosing (0 hr) and 0.5, 1, 2, 3, 4, and 5 hours after dosing to determine indinavir pharmacokinetics. Parameters of interest were maximum plasma concentration (Cmax), time to Cmax, area under the plasma concentration-time curve from 0-5 hours after the dose (AUC0-5), an extrapolated 8-hour AUC (AUC0-8), trough (minimum) plasma concentration (Cmin), and oral clearance. Mean steady-state indinavir Cmax was significantly reduced (20%) after 7 days of vitamin C administration (10.3 ± 1.5 vs 8.2 ± 2.9 µg/ml, p=0.04). The corresponding mean AUC0-8 was also significantly decreased (14%; 26.4 ± 7.2 vs 22.7 ± 8.1 µg hr/ml, p=0.05). Although not statistically significant, the mean indinavir Cmin was 32% lower in the presence of vitamin C (0.27 ± 0.17 C vs 0.18 ± 0.08 µg/ml, p=0.09). Indinavir oral clearance and half-life were not significantly different.
Conclusion: Concomitant administration of high doses of vitamin C can reduce steady-state indinavir plasma concentrations. Subtherapeutic concentrations of antiretroviral agents have been associated with viral resistance and regimen failure, but the clinical significance of our findings remains to be established.

A previous study reported that the popular herbal product St. John's wort taken concomitantly with the antiretroviral agent indinavir significantly reduced plasma indinavir concentration.[1] This was an important first step in highlighting the potential dangers of concurrent use of complementary and alternative medicines with traditional drug therapy. Although consumption of St. John's wort and other herbal products has been reported in patients with human immunodeficiency virus (HIV), most reports indicate that consumption of vitamin C (ascorbic acid) is far more common in these patients.[2] The recommended daily allowance for vitamin C supplementation is approximately 60-90 mg, but patients with HIV often take high daily doses of 1000 mg or more.[3,4,5] Proposed reasons for vitamin C consumption by patients with HIV are enhancement of immune function, reduction of oxidative stress, and possible anti-HIV activity. Despite common use of vitamin C in this population, to our knowledge, information regarding pharmacokinetic interactions between vitamin C and antiretroviral drugs is nonexistent.

The HIV type 1 protease inhibitors are potent antiretroviral agents and are the cornerstones of antiretroviral regimens for many patients.[6] These agents exhibit a strong concentration-effect relationship.[7,8] Thus, maintenance of serum concentrations that suppress viral replication without causing human toxicity is critical. Many of the drugs known to interact with protease inhibitors do so by inhibiting or inducing protease inhibitor metabolism by the cytochrome P450 (CYP) 3A4 isoenzymes or by affecting drug transporters such as P-glycoprotein.[9]

Results from several animal model experiments have shown that vitamin C exerts a modulatory effect on CYP enzyme systems.[10,11,12,13,14] For example, studies in guinea pigs suggest that high doses of vitamin C can induce CYP isoenzymes such as CYP3A.[13,14] Therefore, an investigation of vitamin C's effect on the pharmacokinetics of antiretroviral agents is warranted. The purpose of our study was to determine whether daily administration of high-dose vitamin C significantly alters the steady-state pharmacokinetics of indinavir in healthy subjects.