ABSTRACT
Aim: Chirality of drugs might be associated with safety issues
through pharmacokinetic or pharmacodynamic variations, interactions, or
direct toxicological responses. This study aimed to examine chiral
status of the drugs withdrawn from the market.
Methods: We searched the literature regarding withdrawn drugs
between 1950-2020 due to safety-related issues and identified 395 drugs.
We examined their chirality and assigned into one of three categories:
achiral compound, chiral mixture, and pure enantiomer. We compared their
distribution at ATC-1 level, duration on the market, and adverse drug
reactions leading to their withdrawal.
Results: We identified that 52.4% (n=207) of withdrawn drugs
were achiral, whereas 27.6% (n=109) were chiral mixtures and 20.0%
(n=79) were pure enantiomers. The mean duration on the market was
24.6±27.5 years. The groups did not differ in terms of mean duration on
the market. Chiral mixtures were significantly more withdrawn than were
achirals in cardiovascular system drugs (17.5% vs. 7.7%, p=0.01). In
musculoskeletal system drugs, pure enantiomers were significantly less
withdrawn (2.5%) compared to achirals (12.6%, p=0.01) and chiral
mixtures (11.9%, p=0.03). Hepatotoxicity was significantly less common
in pure enantiomers (5.4%) compared to chiral mixtures (12.7%, p=0.04)
and achirals (17.0%, p<0.01). Cardiovascular toxicity was
significantly more common in chiral mixtures (14.5%) compared to that
in achiral drugs (7.5%, p=0.02).
Conclusion: Our study showed slightly higher representation of
chiral mixtures among withdrawn drugs over pure enantiomers. The
assessment of withdrawal reasons further indicates higher tendency of
chiral mixtures towards hepatotoxicity and cardiovascular toxicity.