Your Prodrug Releases Formaldehyde: Should You Be Concerned? No!

doi:10.1002/jps.21319

Journal of Pharmaceutical Sciences

Volume 97, Issue 10, October 2008, Pages 4184-4193

https://doi.org/10.1002/jps.21319 Get rights and content

ABSTRACT

The title of this commentary contains a frequently asked question whenever someone presents or proposes a prodrug strategy that releases formaldehyde as a result of bioconversion of a prodrug to parent drug. Formaldehyde, a highly water-soluble one-carbon molecule, is endogenous to cells, tissues, and body fluids. Although formaldehyde is generated and incorporated into essential metabolic processes by the human body, exposure to large amounts of formaldehyde vapor can irritate the nasal mucosa and may potentially be carcinogenic. It also gives a positive Ames test. Metabolism of both endogenous and exogenous formaldehyde involves rapid oxidation to formic acid catalyzed by glutathione dependent and independent dehydrogenases in the liver and erythrocytes. Balancing this rapid detoxification pathway is endogenous formation from normal metabolic processes and exogenous formaldehyde input, resulting in approximately 0.1 mM systemic levels. The possibility that formaldehyde released upon bioconversion of prodrugs might induce toxicity has been repeatedly stated, but no convincing evidence for this perceived toxicity has been documented in experimental studies. Therefore, as pharmaceutical chemists and not as toxicologists, we present our perspective on the apparent concern with release of formaldehyde as a by-product of in vivo bioconversion of selective prodrugs, and suggest that in comparison to the total amount of daily endogenous formaldehyde production from metabolism, and exogenous exposure from food and the environment, the amount generated by prodrugs is minute and is unlikely to cause any systemic toxicity in humans. Such an argument does not preclude formaldehyde-based toxicity assessment of a prodrug. Instead, it reduces the risk that in vivo liberation of formaldehyde will cause undue toxicity.

Section snippets

EXPOSURE TO FORMALDEHYDE PER SE AND FORMALDEHYDE FORMED FROM METHANOL

Exposure to humans occurs through inhalation of formaldehyde vapors, direct dermal contact and via dietary sources. The concentration of formaldehyde near the ground in coastal, mountain, or oceanic areas across the world has been estimated to be in the range of 0.05–15 µg/m³,⁵ while indoor and residential concentrations are reported to be 4- to 10-fold higher than those of outdoor air.¹⁵ The major source of indoor exposure to formaldehyde is from pressed wood products,¹⁶ carpets, furniture,

IN VIVO FATE OF FORMALDEHYDE

Formaldehyde is an essential metabolite present in all cells and is produced during the metabolism of glycine, methionine, choline, and serine.³⁹ Its concentration in tissues, cells, and body fluids in both exposed and unexposed mammals and humans is approximately 0.1 mM (2.6 mg/L).^23, ⁴⁰ Since formaldehyde has a very short biological half-life one can estimate what the total daily body exposure or turnover of formaldehyde is from all sources.

Owing to its high solubility in water, formaldehyde

FORMALDEHYDE FROM PRODRUGS

Considering the extensive information on, and the lack of systemic toxicity upon exposure of humans to formaldehyde, it is interesting that concerns have been raised about administration of prodrugs that release formaldehyde as a by-product upon in vivo bioconversion, even though no convincing evidence for this perceived toxicity has been documented in experimental studies. Clearly if toxicity related to formaldehyde release was seen, the FDA and other regulatory agencies would not have

CONCLUSION

Formaldehyde has been linked to, or is perceived to be, the causative agent for a wide range of clinical disorders. Although there are numerous reports attempting to demonstrate a cause-effect relationship between apparent toxicities and exposure to formaldehyde, there are but a few studies, limited to rodents or cell lines, which can support this. A majority of the numerous epidemiological studies on the health risks associated with exposure of humans to formaldehyde have not provided clear

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: Published online in Wiley InterScience (www.interscience.wiley.com).

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CommentarieYour Prodrug Releases Formaldehyde: Should You Be Concerned? No!

ABSTRACT

Section snippets

EXPOSURE TO FORMALDEHYDE PER SE AND FORMALDEHYDE FORMED FROM METHANOL

IN VIVO FATE OF FORMALDEHYDE

FORMALDEHYDE FROM PRODRUGS

CONCLUSION

Atmos Environ

Mutat Res

Regul Toxicol Pharm

Regul Toxicol Pharm

Toxicol Appl Pharm

Fundam Appl Toxicol

Food Chem Toxicol

Toxicol Appl Pharmacol

J Biol Chem

Biochem Pharmacol

Regul Toxicol Pharmacol

Bioorg Med Chem Lett

Biochem Pharmacol

Food Chem

Anal Chim Acta

Impact of oxygenated gasoline use on California light-duty vehicle emissions

Environ Sci Technol

Toxicity to rats of methanol-fueled engine exhaust inhaled continuously for 28 days

J Toxicol Environ Health

Chamber assessment of formaldehyde and VOC emissions from wood-based panels

Indoor Air

Formaldehyde (Environmental Health Criteria 89). International Programme on Chemical Safety

A new metabolite of butylated hydroxyanisole in man

Biopharm Drug Dispos

Pharmacokinetics and metabolism of codeine in humans

Biopharm Drug Dispos

Formaldehyde exposure and respiratory cancer—a meta-analysis of the epidemiologic evidence

Scand J Work Environ Health

Mortality from solid cancers among workers in formaldehyde industries

Am J Epidemiol

Pharyngeal cancer mortality among chemical plant workers exposed to formaldehyde

Toxicol Ind Health

An updated meta-analysis of formaldehyde exposure and upper respiratory tract cancers

J Occup Environ Med

Inhaled formaldehyde: Exposure estimation, hazard characterization, and exposure-response analysis

J Toxicol Environ Health B Crit Rev

Chamber assessment of formaldehyde and VOC emissions from wood-based panels

Indoor Air

Analysis of formaldehyde in tobacco smoke by high performance liquid chromatography

J Chromatogr Sci

Recommendations for and documentation of biological values for use in risk assessment

Reizwirkung des formaldehyds (HCHO) auf den menschen

Int Arch Occup Environ Health

Controlled human studies with formaldehyde

Eye irritation response of humans to formaldehyde

Am Ind Hyg Assoc J

Formaldehyde dose-response in healthy non-smokers

J Air Pollut Control Assoc

Formaldehyde (CH2O) concentrations in the blood of humans and Fischer-344 rats exposed to CH2O under controlled conditions

Am Ind Hyg Assoc J

Commentarie
Your Prodrug Releases Formaldehyde: Should You Be Concerned? No!

Formaldehyde (CH₂O) concentrations in the blood of humans and Fischer-344 rats exposed to CH₂O under controlled conditions