Publications
Product
| 지원과제 | BMRC |
| 저자명 | Bae SK, Park SJ, Shim EJ, Mun JH, Kim EY, Shin JG, Shon JH. |
| 학회정보 | J Clin Pharmacol. 51(3):444-51 / 2011.03 |
| 제 목 | Increased Oral Bioavailability of Itraconazole and Its Active Metabolite, 7-Hydroxyitraconazole, When Coadministered With a Vitamin C Beverage in Healthy Participants. |
| LINK | www.ncbi.nlm.nih.gov/pubmed/20400647 |
| 게시일 | 2014-02-12 13:50:34 |
| 년도 | 2011-International |
| 내용 | Itraconazole is a triazole antifungal agent with a broad spectrum of activity, including activity against a wide variety of Aspergillus and Candida albicans and non-Albicans species, and is generally well tolerated.1–3 As an extremely lipophilic compound, itraconazole is frequently poorly absorbed, with water solubility being the rate-limiting step in itraconazole absorption from the gastrointestinal tract.
Itraconazole is a weak base (pKa = 3.7) with high lipophilicity (log D greater than 5).4 Its aqueous solubility is estimated at approximately 1 ng/mL at neutral pH and approximately 4 μg/mL at pH 1,4 and thus it is ionized and water soluble only at low pHs, as in gastric juice. Itraconazole is available as capsules or an oral solution, and doses of 200 mg daily or 200 mg twice a day are used therapeutically.5 Because it has relatively low bioavailability after oral administration, especially when given in capsule form,6,7 gastric acidity is required for drug dissolution and adequate absorption with capsule formulations. Decreased absorption has been observed in the fasting state and in patients with low gastric acidity.5 Furthermore, in persons with AIDS, the absorption of itraconazole from capsules was reduced by 50% compared with absorption in healthy persons.8 Hypochlorhydria and thus a relatively high gastric pH, a frequent complication of human immunodeficiency virus (HIV) infection, may be responsible for this phenomenon.9 In addition, histamine H2-receptor antagonists such as ranitidine or proton pump inhibitors such as omeprazole10 reduce gastric acidity and cause significant impairment of itraconazole absorption. The coadministration of an acidic beverage (eg, a cola soft drink) effectively improves the bioavailability of itraconazole capsules.11,12 However, there are some disadvantages to using a cola soft drink to achieve maximum absorption. Over the past several decades, increased consumption of sugar-sweetened soft drinks has paralleled an increase in obesity.13,14 Patients with diabetes mellitus or obesity may not be candidates for the use of cola soft drinks. Caffeine is also present in some soft drinks, including colas. It is the most widely used psychoactive substance15,16 and has been considered by some investigators to be a drug of abuse. Caffeine is classified as a stimulant and is typically used for its ability to arouse the central nervous system. Although recognized as safe by the US Food and Drug Administration (FDA), caffeine use in excess can result in serious health hazards and, in rare cases, even death.17,18 Moreover, even with smaller amounts, some caffeine-sensitive individuals may experience mild, temporary effects, including headache, restlessness, and irritability, when their daily intake is quickly and substantially altered. Vitamin C is an essential micronutrient involved in many biological and biochemical functions. Commonly referred to as an antioxidant, vitamin C is one of the body's best defenses against free radicals. Vitamin C is commonly used to prevent the common cold in winter, and regular vitamin C consumption may decrease the duration of cold symptoms in both adults and children.19 Vitamin C is not produced or stored by the body and thus must be replenished daily. A vitamin C beverage drink as a supplement is a healthy and convenient way to consume the recommended daily allowance of essential vitamins, especially vitamin C, and minerals. In Korea, vitamin C beverages marketed by various manufacturers provide a wide dose range. The Vita500 drink, one of the most common beverages in Korea, includes 500 mg of ascorbate and has a pH of 2.7. It was chosen as the acidic, vitamin C-containing beverage for this study. The use of Vita500 offers the advantage of convenience, as it is easy to use and widely available. It has been reported that antacids and colas reduced and increased, respectively, the oral bioavailability of itraconazole; however, there is insufficient information on the effect of altered itraconazole absorption on pharmacokinetic changes of its active metabolite, 7-hydroxyitraconazole. In the liver, itraconazole is extensively processed into many metabolites, via CYP3A4/5; one of these metabolites, 7-hydroxyitraconazole, occurs at plasma levels 2-fold those of itraconazole.6,20 Hydroxyitraconazole was shown to have in vitro antifungal activity comparable to that of itraconazole itself.20 In addition, itraconazole has also been found to be a substrate of P-glycoprotein (P-gp).21 P-gp activity is one important mechanism that decreases the oral bioavailability of drugs by limiting intestinal absorption.22–24 After oral administration of an itraconazole capsule, because of this, its pharmacokinetic properties would be affected by several factors, including its dissolution, the amount and activity of CYP3A4/5, and the P-gp activity in the gastrointestinal tract and/or liver. Thus, to fully understand the mechanism of action and to assess the total antifungal activity in plasma, the simultaneous determination of itraconazole and 7-hydroxyitraconazole levels is necessary. The present study was conducted to investigate the pharmacokinetics of itraconazole and its active metabolite, 7-hydroxyitraconazole, after a single dose of itraconazole 200 mg capsule alone or coadministered with a cola drink or a vitamin C beverage (Vita500). |
