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Orthomolecular Medicine News Service, Feb 10, 2023

New Concepts for Understanding Nutrient Pharmacokinetics: Nutri-kinetics and Nutri-dynamics

Michael J Gonzalez1,2,3, Jorge R Miranda-Massari3,4, Jorge Duconge4, Juan Manuel Martinez5, Jose Olalde6, Michael Joseph Gonzalez6, Miguel J. Berdiel7, Jose Lozada2, Robert G. Smith8, Andrew W. Saul

OMNS (Feb 10, 2023) Although supplements of essential nutrients can have therapeutic potential, they are qualitatively different from drugs. Many drugs are more toxic than micronutrients and have widespread and unique biological qualities. Failure to take into account the multiple functions of essential nutrients and how disease states can dramatically alter micronutrient needs have created design flaws in many studies that have been translated into erroneous interpretations. In this article, we propose the use of the terms nutrikinetics and nutridynamics to better describe and differentiate the metabolic nature of essential nutrients. In addition, we elaborate on the therapeutic window, detoxification, and elimination of essential nutrients. Finally, we also propose the consideration of adequate doses of dietary supplements early in the management of any disease condition, before or at least simultaneous to the use of pharmaceutical medications.

Orthomolecular nutrients vs toximolecular drugs

While many health practitioners consider nutrients and drugs interchangeable when it comes to their effects on the body, there are fundamental metabolic and physiologic processes that show that they are very different from each other.

Vitamins and minerals in therapeutic amounts are indicated for the treatment of deficiency states, for pathologic conditions in which absorption or production of vitamins are reduced, or requirements increase. In orthomolecular medicine, nutrients (mostly essential nutrients) are used as a treatment for non-nutritional disease processes. This is based on the understanding that many chronic and acute conditions are associated with an underlying and fundamental biochemical disruption that can be improved by giving the right molecules, in the right chemical form, at the right amount and rates and by the right route. [1,2]

Two-time Nobel Prize winner Linus Pauling, PhD, coined the term "Orthomolecular" in 1968. Orthomolecular medicine describes the practice of preventing and treating disease by providing the body with optimal amounts of substances which are natural to the body.

The practice of employing a variety of micronutrients in therapeutic amounts has proven successful in many scenarios with the advantages of very low toxicity and mild adverse effects as shown in cancer, [3-5] schizophrenia, [6] cognition and behavior, [7] diabetic peripheral neuropathy, [8] severe stress, [9] and many others.

Many medical and scientific research studies reporting on the use of micronutrients in medical conditions fail to detect a real difference because there are flaws in the design that are related to dose, form, dose rate, or administration route. When utilizing high-dose vitamin/mineral therapy, a major issue is related to the mis-perception that nutrient kinetics/dynamics are similar to drug pharmacokinetics. This misinterpretation has negatively impacted the effective use of high-dose nutrients as therapeutic agents.

Pharmacokinetics and Pharmacodynamics

Pharmacokinetics (PK) is the study of the change in drug and/or metabolite concentrations over time (i.e., kinetics) in the body. [10] In general, PK describes how the body interacts with a specific chemical, including the metabolic changes, and the effects and routes of excretion of the metabolites of the drug. Pharmacokinetic properties of chemicals are determined by their chemical and physical nature (i.e., size, polarity, pKa) and also can be affected by the route of administration and the dose of the administered drug. PK may be simply defined as what the body does to the drug.

Pharmacodynamics (PD) is the branch of pharmacology concerned with the effects of drugs and the mechanism of their action. PD may be defined as what the drug does to the body. [11] Accordingly, PD studies the relationship between drug concentrations and effects and the mode of drug action.

To develop a comprehensive understanding of the kinetics (PK) and dynamics (PD) of a drug it is necessary to have detailed knowledge of a number of factors, such as: including but not limited to their major physical-chemical properties (e.g., molecular size, solubility, logP, pKa), the anatomical and physiological properties, attributes of the "inert" substances included in the drug, the characteristics of the applicable biological membrane barriers in the body, the corresponding membrane transport mechanisms, and the characteristics of the enzymatic reactions that activate or inactivate the drug. These concepts can be incorporated in a mathematical model, which allows a better understanding of how a particular drug will behave in the body and can make predictions about whether or not drug administrations will require dose adjustments to achieve optimal bioavailability. The model can then be used in the clinical application of pharmacokinetic PK and PD concepts. [12] Clinical pharmacokinetics provides many performance guidelines for the effective and efficient use of drugs for medicine.

There is a qualitative difference between the effect of a pharmaceutical drug and the nature of a micronutrient. This seems to be an important source of confusion and misunderstanding regarding dosing and the principles of therapeutic strategies.

Nutrients vs Drugs

Nutrients are biological precursors and mediators of metabolic processes. Their absorption, distribution, metabolism, and excretion proceed according to natural physiological mechanisms. Drugs (pharmaceuticals) by contrast are foreign substances not normally present in the body and their absorption, distribution, metabolism, and excretion proceed via detoxification pathways designed for xenobiotics (i.e. chemicals to which an organism is exposed that are extrinsic to the normal metabolism of that organism).

"No illness which can be treated by diet should be treated by any other means."

(Moses Maimonides, 1135-1204)

Metabolic enzymes catalyze all biochemical reactions in the body. Enzymes make and degrade neurotransmitters, allow for the expression or suppression of genes, make hormones, and facilitate all aspects of metabolism. Both natural and conventional healthcare practitioners seek to understand and influence metabolic enzymes, but in different ways. Drugs and micronutrients have fundamental differences. A key difference is that most drugs work by causing an effect on specific molecules. For example, drugs can function by blocking voltage-dependent ion channels and membrane transporters. Antimicrobials act by disrupting structures or metabolic pathways key to pathogen survival. Many drugs are strong inhibitors of metabolic enzymes, and are intended to have specific and restricted action. Most essential micronutrients, in contrast, work as metabolic enzyme activators and have multiple actions.

There are a few exceptions to this rule, for example, hormone replacement therapy does not directly modulate enzyme activity. Drugs can induce nutrient deficiencies as well as numerous unwanted side effects. Some common medicines used long-term interfere with nutrient availability, such as arthritis pain medications, cholesterol-lowering statins, birth control pills, and antibiotics.

For example, statin drugs block the enzyme that produces cholesterol in the liver, thereby lowering cholesterol. However, other metabolic enzymes are blocked as well, causing weakness, joint pain, insomnia, rashes, muscle pain, headaches, infections, sinusitis, chest pain, and peripheral edema.

While the benefits of utilizing a drug may outweigh the risks, it is important to note that medication usually does not correct the condition which caused a chronic health problem in the first place. Drugs are often designed to take care of the symptom but not the root of the problem.

This highlights a very relevant philosophical difference between orthomolecular medicine vs conventional medicine approaches to health. Orthomolecular medicine works by supplying appropriate levels of essential nutrients to the body's biochemistry to correct the deficiency that leads to the unbalanced state we call disease. [13,14] These characteristics of nutrients vs pharmaceuticals in orthomolecular and conventional medicine are summarized in Table 1.

Table 1.

Table 1: Nutrients vs Pharmaceuticals

In order to mitigate the risk of nutrient deficiency-associated side effects of medication, the diet should be manipulated to provide additional food sources and supplements and essential nutrients. This will generally require higher than RDA levels of essential nutrients as rectification of deficiencies will not be sufficient from diet alone, because the disease process usually increases micronutrient needs. In addition, drug metabolism may also consume additional micronutrients and therefore can cause drug-induced nutrient depletion. [15]

Another important iatrogenic issue is drug-induced mitochondrial dysfunction. Cancer chemotherapeutic agents [16,17] and most medications in general [18,19] that are taken chronically can induce serious mitochondriopathies that can result in liver damage, cardiotoxicity, and neuropathies. Drugs known to cause mitochondrial dysfunction include NSAIDs, Acetaminophen, statins, antidepressants, Metformin and others. These effects can be mitigated by the proper use of micronutrients such as vitamin C, lipoic acid, and N-Acetylcysteine, molecular replacement of membrane lipids and enzymatic cofactors, such as coenzyme Q10. [20] Phytochemicals such as curcumin, quercetin, and polyphenols have been shown to reduce necrotic cell death, restore the antioxidant defense mechanism, limit oxidative stress, and prevent the inflammation of tissue and dysfunction of the mitochondria. [21]

The basis of orthomolecular medicine is providing essential nutrients in adequate doses according to the needs and deficiencies of the body's metabolism. Essential micronutrients are required for the activity of many enzymes. Magnesium is required by several hundred different enzymes, [22} and so is NAD+, supplied by niacin. Essential micronutrients (vitamins, minerals, and other cofactors) from the diet or taken as supplements can therefore promote optimization of many aspects of metabolism.

This qualitative difference in the nature of a pharmaceutical drug and a micronutrient often seems to lead to confusion and misunderstanding. Therefore, we propose the use of the terms "nutrikinetics" and "nutridynamics" to describe how nutrients such as vitamins and minerals enter the bloodstream upon absorption and get distributed to the body's organs. These equilibrate rapidly from blood plasma when they reach highly perfused tissues (e.g. red blood cells, liver, kidney) but more slowly with adipose tissue, skin and poorly perfused organs.

The therapeutic window difference

The therapeutic window for a drug is the relationship between the therapeutic and toxic dose. A generalization we can make for nutrients compared to drugs is that the therapeutic dose for nutrients is much farther below the toxic dose. This is a very powerful argument for nutritional intervention (diet and supplementation) prior to the use of medications as the first line of treatment. Dietary supplements are gentle and safe, containing micronutrients such as vitamins and minerals that contribute to normalizing the underlying biochemical deficiencies caused by disease. Nutrients, therefore, have a broad therapeutic window, and in comparison, pharmaceutical drugs in general have a narrow therapeutic window. (See Figure 1).

Figure 1.

Figure 1: Therapeutic Window

Because of the substantial danger of drug toxicity, prescription errors are of concern. In fact, it has been reported that drug-related iatrogenia in hospitals accounted for 106,000 deaths per year in the United States. [23] In addition, a study in ambulatory patients revealed that drug-related morbidity and mortality was 76 billion in 1995. [24] When the study was repeated 6 years later, that figure increased to 177.4 billion. [25] The cost more than doubled in six years. A third study 17 years later revealed that the cost of prescription Drug-Related Morbidity and Mortality resulting from nonoptimized medication therapy was $528.4 billion. [26]

In comparison, adverse effects of nutritional supplements even with high doses are extremely rare. [27] The AAPCC (The American Association of Poison Control Centers) report shows no deaths from any dietary mineral supplement. There were no fatalities from amino acids, creatine, blue-green algae, glucosamine, or chondroitin. There were no deaths from herbs. [28]


Detoxification is the physiological removal of toxic substances from the human body, which is mainly carried out by the liver by a cascade of enzymatic reactions. However this process takes energy and consumes vitamin cofactors. Substances that easily dissolve in water can be readily excreted from the body bypassing this energy consuming process. The process of detoxification transforms toxic, fat-soluble substances into harmless, water-soluble molecules which can be excreted from the body through the kidneys, bowel, skin, or lungs. Detoxification processes occur in organs like the liver and kidney, as well as inside the cells (specifically, the inner membrane of mitochondria or in the endoplasmic reticulum of cells) in proteins such as Cytochrome enzymes.

Detoxification of foreign substances such as drugs is heavily nutrient-dependent. Some of the key nutrients involved with detoxification include zinc, B-complex vitamins, amino acids such as L-glutamine, taurine, N-acetylcysteine, and many others. Excess hormones, environmental toxicants, and prescription drugs are all cleared via the same enzymatic detoxification systems. Metabolic detoxification is therefore essential for protecting the body from toxic environmental factors and maintaining the internal homeostasis necessary for maintaining a healthy state.

The metabolic detoxification process comprises three essential steps:

Phase I-enzymatic transformation: to chemically transform compounds from lipid-soluble into more water-soluble. Generally carried out by cytochrome P450 (CYP) enzymes.

Phase II-enzymatic conjugation: to further increase water solubility and decrease the reactivity of phase I products. Generally carried out by UDP-glucuronlytransferases (UGTs), glutathione S-transferases (GSTs), and sulfotransferases (SULTs).

Phase III-transport: to excrete water-soluble compounds from the cell. Generally carried out by ATP-binding cassette (ABC) transporters.

It is important to point out that products resulting from Phase I detox are often more toxic than the original compounds. Phase II detox reactions neutralize these products to decrease their toxicity. Several factors, including diet, smoking, consuming alcohol, advanced age, and certain diseases may cause phase II enzymes to become overwhelmed leading to augmented toxicity that may cause an unbalanced disease state.

Deficiencies in vitamins A, B2, B3, B9 (folate), C, and E are linked with decreased phase I activity and can slow the metabolism of certain drugs. B vitamins are also particularly important as cofactors in phase II reactions. Deficiencies in iron, calcium, copper, zinc, magnesium, and selenium have been shown to reduce phase I enzymatic activity. Amino acid deficiencies in sulfur-containing amino acids such as methionine and cysteine can also modulate phase I activity.

A variety of natural products have been shown in vitro or cell culture to directly increase activity of phase II enzymes; these include resveratrol, curcumin, alpha lipoic acid, tocopherols, lycopene, gingko biloba, allyl sulfides from garlic, among others. Other natural interventions that may be helpful for detoxification include calcium-D-glucarate, chlorophyllin, probiotics, and derivatives of quercetin. [29] Phase I, II, and III pathways have different biochemical requirements and respond to different metabolic signals but must work in unison for the proper removal of unwanted xenobiotics (such as natural toxins or drugs). Enzymes of the phase I, II, and III pathways have several characteristics that make them well-suited for their important roles. Unlike most other enzymes, detoxification enzymes can react with many different compounds, are more concentrated in areas of the body that are most directly exposed to the environment (like the liver, intestines, or lungs), and are inducible, meaning that their synthesis can be increased in response to toxin exposure. Their activity is cofactor availability dependent (vitamins and minerals).


Elimination is the removal of a substance from the body. This can be accomplished through a metabolic pathway, where the substance is broken down into inactive metabolites, or through excretion. The liver is the primary site of phase I and phase II biotransformation. There are many different routes of excretion, including urine, bile, sweat, saliva, tears, milk, and stool. By far, the most important excretory organs are the kidney and liver.

The kidneys are an important organ involved in the elimination of drugs and their metabolites. Substances excreted in the feces usually involve orally ingested unabsorbed drugs or metabolites excreted in the bile that is not reabsorbed from the intestinal tract. Excess vitamins and minerals are normal physiologically friendly constituents of metabolism which are natural to the body, and can often be eliminated by just increasing hydration.


Synthetic drug compounds can disrupt important biologic processes and are therefore presumed unsafe. They are required by law to undergo an elaborate testing and must meet specific criteria to demonstrate their safety at a specific dose and frequency, for a particular period of time in a specific condition. Dietary supplements are considered safe and have a lower incidence of serious adverse reactions than drugs. Further, when using pharmaceutical drugs, the concomitant use of nutritional agents may result in better outcomes by reducing drug-induced nutrient depletion mitigating resulting biochemical dysfunction.

The basis of orthomolecular medicine is correcting "imbalances, insufficiencies or deficiencies based on cellular biochemistry" to treat disease by use of essential nutrients such as vitamins, minerals, amino acids, and fatty acids. The term "metabolic correction" has been defined as physiological optimization of an individual using diet and essential micronutrients to achieve a healthy state. [13,14] The rate and extent of the enzymatic activity that determines these processes depend on the bioavailability (active form, appropriate quantity) of these micronutrients. Metabolic correction increases enzymatic function and can enhance biological functions contributing to better overall health and well-being. To take full advantage of this health paradigm we must understand the intrinsic biochemical-physiological mechanisms involved. The use of essential nutrients given at appropriate doses is a very relevant, physiologically friendly, nontoxic therapeutic tool.

Authors' affiliations:

University of Puerto Rico, Medical Sciences Campus, School of Public Health1, San Juan, Puerto Rico; Universidad Central del Caribe, School of Chiropractic2, Bayamon, Puerto Rico; EDP University, Program of Naturopathic Sciences3, Hato Rey, Puerto Rico; University of Puerto Rico, Medical Sciences Campus, School of Pharmacy4, San Juan, Puerto Rico; Ortho-Regenerative Medicine5, Chía, Colombia; Centro Médico Regenerativo6, Bayamon, Caguas, Puerto Rico; Berdiel Clinic7, Ponce, Puerto Rico. University of Pennsylvania, Department of Neuroscience 8.

Corresponding author: Michael J Gonzalez, DSc, NMD, PhD, FANMA, FACN, Professor; University of Puerto Rico, Medical Sciences Campus, School of Public Health.


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9. Pouteau E, Kabir-Ahmadi M, Noah L, et al. (2018). Superiority of magnesium and vitamin B6 over magnesium alone on severe stress in healthy adults with low magnesemia: A randomized, single-blind clinical trial. PloS One, 13(12), e0208454.

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14. Gonzalez MJ, Olalde J, Rodriguez JR, Rodriguez, Duconge J. (2018) Metabolic Correction and Physiologic Modulation as the Unifying Theory of the Healthy State: The Orthomolecular, Systemic and Functional Approach to Physiologic Optimization. J Orthomolec Med 33(1).

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16. Varga ZV, Ferdinandy P, Liaudet L, Pacher P. (2015). Drug-induced mitochondrial dysfunction and cardiotoxicity. Am J Physiol Heart Circ Physiol. 309:H1453-H1467.

17. Doyle TM, Salvemini D. (2021). Mini-Review: Mitochondrial dysfunction and chemotherapy-induced neuropathic pain. Neuroscience letters, 760, 136087.

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19. Vuda M & Kamath A. (2016). Drug-induced mitochondrial dysfunction: Mechanisms and adverse clinical consequences. Mitochondrion, 31:63-74.

20. Nicolson GL, Conklin KA. (2008). Reversing mitochondrial dysfunction, fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy. Clin Exp Metastasis. 25:161-169.

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22. Schwalfenberg GK, Genuis SJ. (2017). The Importance of Magnesium in Clinical Healthcare. Scientifica, 2017:4179326.

23. Lazarou J, Pomeranz BH, Corey PN. (1998). Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA, 279:1200-1205.

24. Johnson JA, Bootman JL (1995). Drug-related morbidity and mortality. A cost-of-illness model. Arch Intern med. 155:1949-1956.

25. Ernst FR, Grizzle AJ. (2001). Drug-related morbidity and mortality: updating the cost-of-illness model. J Am Pharm Assoc. (Wash) 41:192-199.

26. Watanabe JH, McInnis T, Hirsch JD. (2018). Cost of Prescription Drug-Related Morbidity and Mortality. The Annals of pharmacotherapy, 52:829-837.

27. Saul AW (2019) No deaths from Vitamins. Orthomolecular Medicine News Service

28. Gummin DD, Mowry JB, Beuhler MC, Spyker DA, Brooks DE, Dibert KW, Rivers LJ, Pham N, Ryan ML. (2020). 2019 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 37th Annual Report. Clinical toxicology (Philadelphia, Pa.), 58:1360-1541.

29. Jakoby WB, Ziegler DM (1990). The enzymes of detoxication, J Biol Chem. 265:20715-20718.

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Albert G. B. Amoa, MB.Ch.B, Ph.D. (Ghana)
Seth Ayettey, M.B., Ch.B., Ph.D. (Ghana)
Ilyès Baghli, M.D. (Algeria)
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Hugo Galindo, M.D. (Colombia)
Martin P. Gallagher, M.D., D.C. (USA)
Michael J. Gonzalez, N.M.D., D.Sc., Ph.D. (Puerto Rico)
William B. Grant, Ph.D. (USA)
Claus Hancke, MD, FACAM (Denmark)
Tonya S. Heyman, M.D. (USA)
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Juan Manuel Martinez, M.D. (Colombia)
Mignonne Mary, M.D. (USA)
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Jorge R. Miranda-Massari, Pharm.D. (Puerto Rico)
Karin Munsterhjelm-Ahumada, M.D. (Finland)
Tahar Naili, M.D. (Algeria)
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