Background: In clinical practice, chloroquine and hydroxychloroquine are often co-administered
with other drugs in the treatment of malaria, chronic inflammatory diseases, and COVID-19. Therefore, their
metabolic properties and the effects on the activity of cytochrome P450 (P450, CYP) enzymes and drug transporters
should be considered when developing the most efficient treatments for patients.
Methods: Scientific literature on the interactions of chloroquine and hydroxychloroquine with human P450 enzymes
and drug transporters, was searched using PUBMED.Gov (https://pubmed.ncbi.nlm.nih.gov/) and the
ADME database (https://life-science.kyushu.fujitsu.com/admedb/).
Results: Chloroquine and hydroxychloroquine are metabolized by P450 1A2, 2C8, 2C19, 2D6, and 3A4/5 in
vitro and by P450s 2C8 and 3A4/5 in vivo by N-deethylation. Chloroquine effectively inhibited P450 2D6 in
vitro; however, in vivo inhibition was not apparent except in individuals with limited P450 2D6 activity. Chloroquine
is both an inhibitor and inducer of the transporter MRP1 and is also a substrate of the Mate and MRP1
transport systems. Hydroxychloroquine also inhibited P450 2D6 and the transporter OATP1A2.
Conclusions: Chloroquine caused a statistically significant decrease in P450 2D6 activity in vitro and in vivo,
also inhibiting its own metabolism by the enzyme. The inhibition indicates a potential for clinical drug-drug interactions
when taken with other drugs that are predominant substrates of the P450 2D6. When chloroquine and
hydroxychloroquine are used clinically with other drugs, substrates of P450 2D6 enzyme, attention should be
given to substrate-specific metabolism by P450 2D6 alleles present in individuals taking the drugs.