International unit

This article is about the pharmacological unit. It is not to be confused with International System of Electrical and Magnetic Units, International System of Units, or international unit of enzyme activity.

In pharmacology, the international unit (IU) is a unit of measurement for the effect or biological activity of a substance, for the purpose of easier comparison across similar forms of substances. International units are used to quantify vitamins and biologics (hormones, some medications, vaccines, blood products and similar biologically active substances).

Multivitamins nutrition facts label showing that the international unit of, for example, vitamins D and E correspond to different gram values

International units as used in pharmacology are not part of the International System of Units (SI).^[1]

For biologic preparations

 

30 IU of oxytocin for intravenous infusion

Biologics are medications and other products made from biological sources. Depending on the form (powder vs solution), production method, or just batch-to-batch differences, there is often some variation in their relative potencies, so that a simple measure of mass would not suffice. The international unit allows one to compare the relative potency of all these forms, so that different forms or preparations with the same biological effect will contain the same number of IUs. To do so, the WHO Expert Committee on Biological Standardization (WHO ECBS) provides a reference preparation of the agent, arbitrarily sets the number of IUs contained in that preparation, and specifies a biological assay procedure to compare other preparations of the same agent to the reference preparation. Since the number of IUs contained in a new substance is arbitrarily set, there is no equivalence between IU measurements of different biological agents.

Process of definition

To define the IU for a substance, an international collaborative study is organized by the WHO Expert Committee on Biological Standardization using various assay systems in several laboratories.^[2] The main goal of the study is to reach a consensus regarding methods of analysis and the approach to standardization so that results can be compared.^[3][4][5]

The study is performed using highly purified preparations of the substance, typically in lyophilized form, called "international reference preparations" or IRPs.^[2] Each preparation is divided into precisely weighed samples, with each sample stored in its own ampoule labeled with a code corresponding to the source IRP.^[2] Assays are performed using these samples and are calibrated against the previously available IU standard. These results can be quite variable; the final IU value for samples of a given IRP are determined by consensus.^[3] The IRP that provides the best results and shows the best long term stability is selected to define the next IU.^[2] This IRP is then referred to as the "international standard".^[2]

When a standard sample comes close to depleting, a new standard will have to be found. A new batch of the substance in question is produced and calibrated against the old one, so that the unit still represents the same amount of biological activity. Many substances have undergone several such standard sample changes. The "third international standard" of prolactin has nearly ran out and was proposed to be replaced in 2016.^[6]

Examples

• 1 IU of rhEGF is defined as the potency of 0.001 μg of a rhEGF in the "91/530" standard vial. One manufacturer reports that its rhEGF is 1.4 times as potent as the 91/530 standard.^[7]
• 12.5 IU of oxytocin is defined as the potency of 21 μg of pure peptide in the "76/575" standard vial.^[8]

Before the purification of penicillin was perfected, the amounts were also described in "International Units" (and some non-international arbitrary "units" before them) to account for batch-to-batch variation. See Penicillin § Penicillin units.

For vitamins

A number of vitamins have distinct vitamers of distinct biological potencies. There is a system in place also called the "international unit" to describe the relative strength of these different molecular forms. Like the biological "international unit", the IU for vitamins is also an arbitrary number that cannot be interconverted among different types of activities. By 1934, the WHO (then the "League of Nations Health Organisation") had already defined the international units for vitamins A, B1, C, and D.^[9]

Unlike biologic preparations, small molecules like vitamins can be very easily purified to yield products that are equivalent in potency. As a result, a simple mass conversion (as opposed to an assay) suffices to obtain the IU:

• 1 IU Vitamin A = 0.3 μg retinol (~0.1 nmol) = 0.6 μg beta-carotene^[10][11][a]
• 1 IU Vitamin D = 0.025 μg D₂/D₃ ≈ 0.65 pmol^[12]
• 1 IU Vitamin E = 2⁄3 mg d-alpha-tocopherol = 0.90 mg of dl-alpha-tocopherol^[10][b]

History

In 1931, the Permanent Commission on Biological Standardisation of the League of Nations Health Organisation specified the provisional standards for vitamins A, B1, C, and D. These original standards were quite crude by modern measures: the standard for vitamin A was a mixture of many caretinoids,^[13] for vitamin B₁ the result of adsorbing rice polishings onto fuller's earth, for vitamin C a sample of lemon juice, for vitamin D a sample of irradiated ergosterol in oil. In 1935, the standards for A, C, and D were changed to use pure substances: pure beta-carotene in oil, crystalline ascorbic acid, and crystalline ergocalciferol.^[9] This same commission also established early standards for biologics (antitoxins, insulins, pituitary extract and sex hormones) in the interwar period.^[14]

In 1944, officials from the League of Nations, in cooperation with the Royal Society, established a first international standard for penicillin.^[14] The postwar World Health Organization established a second standard in 1953. Both were defined using a pure, crystalline substance.^[15]

Languages

The name international unit is often capitalized in English and other languages, although major English-language dictionaries treat it as a common noun and thus use lower case.^[1] The name has several accepted abbreviations. It is usually abbreviated as IU in English, and UI in Romance languages (for example Spanish unidad internacional, French unité internationale, Italian unità internazionale, Romanian unitate internațională), IE in several Germanic languages (for example German internationale Einheit, Dutch internationale eenheid) or as other forms (for example Russian МЕ, международная единица [mezhdunarodnaya yedinitsa], Hungarian NE, nemzetközi egység).^{[citation needed]}

In order to remove the possibility of having the letter "I" confused with the digit "1", some hospitals have it as a stated policy omit the "I", that is, to only use U or E when talking and writing about dosages, while other hospitals require the word "units" (or words "international units") to be written out entirely.^[16] (For example, "three international units per litre" may be abbreviated "3 U/L". The "liter" sign (L) is less affected, as less confusing written forms are used.)

See also

• United States Pharmacopeia (USP)

References

Notes

1. The IU/RE equvalency has been replaced by the RAE conversion. See Vitamin A § Equivalencies of retinoids and carotenoids (IU).^[10]
2. The US NIH has replaced IU with mg d-alpha-tocopherol equiv. See Vitamin E § Food labeling.^[10]

Citations

1. "international unit". Oxford English Dictionary (Online ed.). Oxford University Press. (Subscription or participating institution membership required.)
2. Canadian Society of Clinical Chemists (Dec 1992). "Canadian Society of Clinical Chemists position paper: standardization of selected polypeptide hormone measurements". Clin. Biochem. 25 (6): 415–24. doi:10.1016/0009-9120(92)90030-V. PMID 1477965.
3. Jeffcoate SL (1988). "What are we measuring in gonadotropin assays?". Acta Endocrinol Suppl (Copenh). 288: 28–30. PMID 3048031.
4. Wicher JT (1991). "Calibration is the key to immunoassay but the ideal calibrator is unattainable". Scand J Clin Lab Invest Suppl. 205: 21–32. doi:10.3109/00365519109104599. PMID 1947745.
5. Ekins R (1991). "Immunoassay standardization". Scand J Clin Lab Invest Suppl. 205: 33–46. doi:10.3109/00365519109104600. PMID 1947747.
6. Ferguson, Jackie (2016). "WHO International Collaborative Study of the Proposed 4th International Standard for Prolactin, Human".
7. "Unit Conversion Table". R&D Systems.
8. "WHO International Standard OXYTOCIN 4th International Standard NIBSC code: 76/575 Instructions for use (Version 4.0, Dated 30/04/2013)" (PDF). nibsc.org.
9. "Vitamin Standards". Nature. 135 (3413): 516–517. March 1935. Bibcode:1935Natur.135..516.. doi:10.1038/135516a0.
10. "Unit Conversions". National Institutes of Health. Retrieved 2018-11-21.
11. Dietary Reference Intakes Tables: Unit Conversion Factors
12. "Vitamin D: Fact Sheet for Health Professionals". Retrieved 6 January 2018.
13. "Standardisation and Estimation of Vitamin A". The Lancet. 226 (5858): 1307. December 1935. doi:10.1016/S0140-6736(00)47376-9.
14. Hartley, Percival (22 June 1945). "World Standard and Unit for Penicillin". Science. 101 (2634): 637–638. Bibcode:1945Sci...101..637H. doi:10.1126/science.101.2634.637. PMID 17844083.
15. Humphrey JH, Musset MV, Perry WL (1953). "The second international standard for penicillin". Bulletin of the World Health Organization. 9 (1): 15–28. PMC 2542105. PMID 13082387.
16. (PDF). The Joint Commission. Archived from the original (PDF) on March 10, 2013. Retrieved 30 May 2013.

External links

 

Look up international unit in Wiktionary, the free dictionary.

• WHO reference preparations
• Online converter with authoritative references for all substances

League of Nations archives:

• Sub-sub-series R850-R852/12B/26142 - Standardisation of Biological Products - UN Geneva archives
• Sub-sub-series R6214-R6216/8E/2887 - Permanent Commission on Biological Standardisation - UN Geneva archives
• Bulletin of the Health Organization, volumes 6–11 - National Library of Scotland