Abstract
Vitamins are crucial for sustaining life because they play an essential role in numerous physiological processes. Vitamin deficiencies can lead to a wide range of severe health issues. In this context, there is a need to administer vitamin supplements through appropriate routes, such as the oral route, to ensure effective treatment. Therefore, understanding the pharmacokinetics of vitamins provides critical insights into absorption, distribution, and metabolism, all of which are essential for achieving the desired pharmacological response. In this review paper, we present information on vitamin deficiencies and emphasize the significance of understanding vitamin pharmacokinetics for improved clinical research. The pharmacokinetics of several vitamins face various challenges, and thus, this work briefly outlines the current issues and their potential solutions. We also discuss the feasibility of enhanced nanocarrier-based pharmaceutical formulations for delivering vitamins. Recent studies have shown a preference for nanoformulations, which can address major limitations such as stability, solubility, absorption, and toxicity. Ultimately, the pharmacokinetics of pharmaceutical dosage forms containing vitamins can impede the treatment of diseases and disorders related to vitamin deficiency.
Introduction
Vitamins are a specific group of organic compounds essential for bodily metabolic processes, as they cannot be produced in sufficient quantities by the body and must be obtained from the diet at trace levels (<1 g/day) (Borel & Desmarchelier, 2018; Combs & McClung, 2016). Other necessary nutrients, such as dietary minerals, essential fatty acids, and essential amino acids, are not included in the term “vitamin,” nor does it encompass a wide variety of other nutrients that support health but are consumed less frequently. Today, the common term “vitamin” is part of everyday language, emphasizing the connection between diet and health. Vitamin deficiencies remain a global concern. They often go clinically unnoticed unless they reach severe levels, but even mild deficiencies can have significant consequences. Vitamin deficiencies can affect individuals of all ages, but they are particularly common in pregnant and breastfeeding women, as well as young children, who have increased requirements for these nutrients and are more susceptible to their absence. These consequences encompass outcomes such as increased susceptibility to infectious diseases, anemia, maternal mortality, impaired cognitive development, and hindered physical growth (Griffiths, 2020).
The World Health Organization (WHO) estimates that over two billion people worldwide suffer from micronutrient deficiencies. Among them, approximately 149 million children under the age of 5 are estimated to be stunted, 45 million are estimated to be wasted, and 38.9 million are overweight or obese. These conditions may be attributed, in part, to a lack of essential vitamins such as vitamin A, vitamin D, various B vitamins, and essential minerals (Darnton-Hill, 2019; Keats et al., 2021). Vitamin inadequacies have a much greater impact on women’s health and reproductive outcomes than was previously understood (Darnton-Hill, 2019). As a result, vitamins have been recognized as essential nutrients that must be acquired through the diet to maintain good health and treat deficiencies. Dietary Reference Intakes (DRIs) provide recommended guidelines for the dietary intake of micronutrients. These standards were established in 1997 by the Food and Nutrition Board of the Institute of Medicine. The committee panel endorses recommendations regarding food intake, nutrition, and the quantitative requirements of vitamins. The reports generated by the DRIs are intentionally designed with a focus on ensuring the safety and quality of nutrients (Institute of Medicine, 2011).
The pivotal role of vitamins is to function as coenzymes, facilitating the transformation of apoenzymes into holoenzymes, thereby regulating both catabolic and anabolic reactions. Several water-soluble vitamins serve as coenzyme (Freeland-Graves & Bavik, 2003). The categorization of vitamins based on their solubility is a fundamental concept in nutrition and biochemistry. Vitamins are essential organic compounds that the human body requires in small quantities for various metabolic and physiological processes. Their solubility plays a crucial role in how they are absorbed, transported, and utilized by the body. Table 1 summarizes the brief summary of vitamins. In short, there are two primary categories of vitamins based on solubility: water-soluble vitamins and fat-soluble vitamins. Water-soluble vitamins: These vitamins dissolve in water and are not stored to a significant extent in the body. Instead, they are readily absorbed in the small intestine and are transported through the bloodstream. Any excess water-soluble vitamins that the body does not immediately use are typically excreted in the urine. The water-soluble vitamins include vitamin B1 (thiamine), B2 (riboflavin), B3 (niacin), B5 (pantothenic acid), B6 (pyridoxine), B8 (biotin), B9 (folic acid), B12 (cobalamin), and vitamin C (ascorbic acid). These vitamins play vital roles in processes like energy metabolism, cell growth, and immune function. Fat-soluble vitamins, on the other hand, do not dissolve in water but are soluble in fats and oils. Unlike water-soluble vitamins, fat-soluble vitamins are stored in the body’s fatty tissues and liver. This storage allows the body to draw upon these reserves when dietary intake is insufficient. The fat-soluble vitamins include vitamin A (retinol), vitamin D (calciferol), vitamin E (tocopherol), and vitamin K (phylloquinone). These vitamins are essential for various functions, such as vision, bone health, antioxidant defense, and blood clotting. Understanding the solubility of vitamins is crucial because it impacts their absorption, transportation, and storage within the body. While both types of vitamins are essential for health, it is important to maintain a balanced diet that provides an adequate supply of both water-soluble and fat-soluble vitamins to support overall well-being and prevent deficiencies (Fitzpatrick et al., 2012).
Furthermore, the classification of vitamins is based on their biological and chemical activity. Consequently, the term “vitamin” may encompass various vitamin compounds, all of which exhibit biological activity associated with a specific vitamin. For instance, “vitamin A” encompasses compounds such as retinal, retinol, and numerous carotenoids. It is important to note that vitamins can undergo interconversion within the human body (Bhagavan, 2002; Combs & McClung, 2016). Fat-soluble vitamins are typically absorbed into the lacteals of the small intestine via chylomicrons with the assistance of bile salts. They are then transported through the lymphatic system and eventually released into the bloodstream (Karunaratne et al., 2017). Fat-soluble vitamins are often stored in the liver or fatty tissues of our bodies until needed, which means they do not typically require frequent ingestion (Coulston et al., 2001). The absorption, transport, activation, and utilization of these fat-soluble vitamins involve enzymes or other proteins whose synthesis is genetically controlled (Bhagavan & Ha, 2015). A deficiency in one of these proteins can result in a disease that closely resembles the effects of a dietary deficiency (as shown in Table 1). Vitamin A, especially in the form of carotenoids such as α- and β-carotene, and β-cryptoxanthin, can be enzymatically converted into retinol in the human body. This conversion is facilitated by the enzyme β-carotene oxygenase 1 (BCO1), and as a result, these compounds are referred to as pro-vitamin A (proVA) carotenoids.
Vitamin D exists in two primary forms: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol), both of which are essential for various physiological functions (see structures in Table 1) (Borel & Desmarchelier, 2018). In humans, the synthesis of vitamin D through exposure to sunlight is highly variable and depends on numerous factors, including the duration of sun exposure, season, clothing, time of day, latitude, atmospheric conditions, sunscreen use, and skin pigmentation. However, a significant proportion of people rely on dietary vitamin D from food supplements to meet their specific needs (Hill et al., 2012). Similar to vitamin A, vitamin D is a pro-hormone that becomes active after undergoing two hydroxylations in the liver (Borel & Desmarchelier, 2018). Vitamin D plays a critical role in maintaining bone health and regulating blood calcium levels. Additionally, it is involved in various other biological functions, including immune response, cell apoptosis, and cell proliferation.
The fat-soluble antioxidant metabolite known as “vitamin E” is a crucial dietary component that includes tocopherol and tocotrienols. Each of these naturally occurring compounds consists of four isomers (α, β, γ, and δ) determined by the position and number of methyl groups on the chromanol ring. While a diet rich in γ-tocopherol serves as the primary source of vitamin E, α-tocopherol predominates in the bloodstream and is associated with various biological activities in humans. Vitamin E undergoes metabolism in the liver, and only α-tocopherol is resecreted into the bloodstream, a process facilitated by the hepatic α-tocopherol transfer protein (α-TTP). This protein plays a critical role in maintaining a stable level of α-tocopherol in the blood, which is essential because defects in the α-TTP gene can result in vitamin E deficiency (Eggermont, 2006). Another fat-soluble vitamin, vitamin K, acts as a coenzyme in the post-translational carboxylation of glutamate residues in multiple proteins, leading to the activation of various proteins, including coagulation factors such as VII, IX, X, and prothrombin (Shearer et al., 2012).
Water-soluble vitamins constitute a diverse group of organic compounds that share the common characteristic of being essential for normal cellular functions. In contrast to fat-soluble vitamins, water-soluble vitamins are not stored in the body and must be regularly included in the diet to prevent deficiency. There are nine water-soluble vitamins: the B vitamins (folate, thiamine, riboflavin, niacin, pantothenic acid, biotin, vitamin B6, vitamin B12) and vitamin C. A deficiency in any of these water-soluble vitamins can lead to clinical syndromes with the potential for severe morbidity and mortality (Lykstad & Sharma, 2021). These vitamins are readily absorbed by enterocytes in the small intestine through membrane transport processes. The absorption of vitamin B12, also known as cobalamin (Cbl), involves multiple processes, including the use of at least four different binding proteins for its journey from the stomach to the ileum (Halsted, 2003). Hence, the gastrointestinal system plays a critical role in preserving and regulating the body’s micronutrient homeostasis. Reduced absorption of these compounds within the intestines can result in vitamin deficiency (Said, 2004a). Furthermore, water-soluble vitamins serve as essential enzyme cofactors in a wide range of metabolic reactions. Riboflavin, niacin, and vitamin C are pivotal in redox reactions, while thiamine and biotin play roles in macronutrient metabolism. Folate, vitamin B12, pyridoxine, and riboflavin are significant contributors to the regulation of S-adenosylmethionine production and DNA synthesis (Halsted, 2003). This review aims to provide an overview of the current understanding of vitamin pharmacokinetics, including factors influencing their biodistribution, and emphasizes the importance of pharmacokinetic analysis for more robust clinical studies. It is worth noting that limited information is currently available regarding the pharmacokinetics of these various vitamins. We hope that this will encourage further research into the pharmacokinetics of vitamins in both health and disease contexts.
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Vrashabh V. Sugandhi, Rudra Pangeni, Lalitkumar K. Vora, Sagun Poudel, Sopan Nangare, Satveer Jagwani, Dnyandev Gadhave, Chaolong Qin, Anjali Pandya, Purav Shah, Kiran Jadhav, Hitendra S. Mahajan, Vandana Patravale, Pharmacokinetics of vitamin dosage forms: A complete overview, Received: 25 April 2023 | Revised: 7 October 2023 | Accepted: 11 October 2023, DOI: 10.1002/fsn3.3787
