Key result
Heritable OCT1 deficiency is linked to ~90% greater systemic fenoterol exposure and stronger hemodynamic effects.
Why the study?
Heritable deficiency of the liver organic cation transporter 1 (OCT1) may affect fenoterol plasma concentrations and toxicity, which is clinically relevant due to fenoterol's severe adverse reactions.
Does heritable OCT1 deficiency increase systemic exposure and cardiovascular/metabolic adverse reactions to fenoterol in healthy individuals?
Observational (n=39)
Does heritable OCT1 deficiency increase systemic exposure and cardiovascular/metabolic adverse reactions to fenoterol in healthy individuals?
Effect estimate: 1.9-fold greater
p-value: p=4.0 x 10^-5
Heritable OCT1 deficiency significantly increases fenoterol plasma concentrations and exacerbates its cardiovascular and metabolic adverse effects, potentially explaining excess mortality associated with the drug.
May warrant OCT1 testing before fenoterol; leaves open confirmation of clinical outcomes in patients.
Fenoterol is a widely used anti‐asthmatic and tocolytic agent, but high plasma concentrations of fenoterol may lead to severe and even fatal adverse reactions. We studied whether heritable deficiency of the liver organic cation transporter 1 (OCT1), a trait observed in 3% of Europeans and white Americans, affects fenoterol plasma concentrations and toxicity. OCT1 transported fenoterol with high affinity, and OCT1 inhibition in human hepatocytes reduced fenoterol uptake threefold. After administration of 180 µg of fenoterol to 39 healthy individuals, the OCT1‐deficient individuals (zero active OCT1 alleles; n = 5) showed 1.9‐fold greater systemic fenoterol exposure ( P = 4.0 × 10 −5 ) and 1.7‐fold lower volume of distribution ( P = 8.0 × 10 −5 ). Correspondingly, the OCT1‐deficient individuals had a 1.5‐fold stronger increase in heart rate ( P = 0.002), a 3.4‐fold greater increase in blood glucose ( P = 3.0 × 10 −5 ), and significantly lower serum potassium levels. In conclusion, heritable OCT1 deficiency significantly increases plasma concentrations of fenoterol and may be an important factor underlying the excess mortality associated with fenoterol.
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Tzvetkov et al. (2017) conducted an observational in Healthy individuals (n=39). Heritable OCT1 deficiency vs. Individuals with active OCT1 alleles was evaluated on Systemic fenoterol exposure (1.9-fold greater, p=4.0 x 10^-5). Heritable OCT1 deficiency resulted in a 1.9-fold greater systemic fenoterol exposure (P=4.0x10^-5) and significantly stronger increases in heart rate and blood glucose.
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