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Identification and Mechanistic Investigation of Drug – Drug Interactions Associated With Myopathy: A Translational Approach

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ABSTRACT

Myopathy is a group of muscle diseases that can be induced or exacerbated by drug–drug interactions (DDIs). We sought to identify clinically important myopathic DDIs and elucidate their underlying mechanisms. Five DDIs were found to increase the risk of myopathy based on analysis of observational data from the Indiana Network of Patient Care. Loratadine interacted with simvastatin (relative risk 95% confidence interval [CI] = [1.39, 2.06]), alprazolam (1.50, 2.31), ropinirole (2.06, 5.00), and omeprazole (1.15, 1.38). Promethazine interacted with tegaserod (1.94, 4.64). In vitro investigation showed that these DDIs were unlikely to result from inhibition of drug metabolism by CYP450 enzymes or from inhibition of hepatic uptake via the membrane transporter OATP1B1/1B3. However, we did observe in vitro synergistic myotoxicity of simvastatin and desloratadine, suggesting a role in loratadine–simvastatin interaction. This interaction was epidemiologically confirmed (odds ratio 95% CI = [2.02, 3.65]) using the data from the US Food and Drug Administration Adverse Event Reporting System.

No MeSH data available.


(a) Dose–response curves of simvastatin (orange), tegaserod (blue), and desloratadine (pink). Healthy, fully differentiated rat L6 myotubes were treated with individual drugs at various concentrations for 5 days, and myotube viability was determined using MTS/PMS assays. (b) Concentration–effect curves of simvastatin in the presence of various fixed concentrations of desloratadine at various concentrations. (d) Concentration–effect curves of desloratadine in the presence of various fixed concentrations of simvastatin. (c) Combination index (CI) – fractional myotube death (fa) plot. CI = 1 indicates additivity (no interaction). The points above 1 indicate antagonism and those below indicate synergism. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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cpt150-fig-0001: (a) Dose–response curves of simvastatin (orange), tegaserod (blue), and desloratadine (pink). Healthy, fully differentiated rat L6 myotubes were treated with individual drugs at various concentrations for 5 days, and myotube viability was determined using MTS/PMS assays. (b) Concentration–effect curves of simvastatin in the presence of various fixed concentrations of desloratadine at various concentrations. (d) Concentration–effect curves of desloratadine in the presence of various fixed concentrations of simvastatin. (c) Combination index (CI) – fractional myotube death (fa) plot. CI = 1 indicates additivity (no interaction). The points above 1 indicate antagonism and those below indicate synergism. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Mentions: We hypothesized that the DDIs identified previously may result from, at least in part, the inhibition of OATP1B1/1B3 that leads to impaired hepatic uptake and compromised hepatic clearance. We first evaluated the potential of the drugs, as well as their pharmacologically active metabolites, to inhibit the active uptake of β‐estradiol 17‐β‐D‐glucuronide (E217βDG) in cryopreserved rat hepatocytes. E217βDG is a relatively specific substrate of OATP1B2, a functional homolog of human OATP1B1/1B3 with very similar substrate specificity.17, 20 At 100 μM, simvastatin acid, omeprazole, alprazolam, desloratadine (the active metabolite of loratadine), simvastatin, tegaserod, ropinirole, loratadine, and promethazine inhibited E217βDG uptake by 103.3 ± 0.5%, 60.1 ± 4.8%, 54.5 ± 0.3%, 44.9 ± 14.2%, 36.3 ± 6.0%, 24.6 ± 15.3%, 23.7 ± 2.7%, 18.1 ± 10.9%, and 17.7 ± 7.7%, respectively. We then determined the inhibitory potencies of the drugs showing ≥45% inhibition. The IC50s (95% CI) of simvastatin acid, omeprazole, alprazolam, and desloratadine were 4.3 μM (3.5, 5.3), 84.3 μM (49.8, 142.9), 99.5 μM (79.5, 124.6), and 140.5 (111.4, 177.1) μM, respectively (inhibition curves are shown in Supplementary Figure1).


Identification and Mechanistic Investigation of Drug – Drug Interactions Associated With Myopathy: A Translational Approach
(a) Dose–response curves of simvastatin (orange), tegaserod (blue), and desloratadine (pink). Healthy, fully differentiated rat L6 myotubes were treated with individual drugs at various concentrations for 5 days, and myotube viability was determined using MTS/PMS assays. (b) Concentration–effect curves of simvastatin in the presence of various fixed concentrations of desloratadine at various concentrations. (d) Concentration–effect curves of desloratadine in the presence of various fixed concentrations of simvastatin. (c) Combination index (CI) – fractional myotube death (fa) plot. CI = 1 indicates additivity (no interaction). The points above 1 indicate antagonism and those below indicate synergism. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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Related In: Results  -  Collection

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cpt150-fig-0001: (a) Dose–response curves of simvastatin (orange), tegaserod (blue), and desloratadine (pink). Healthy, fully differentiated rat L6 myotubes were treated with individual drugs at various concentrations for 5 days, and myotube viability was determined using MTS/PMS assays. (b) Concentration–effect curves of simvastatin in the presence of various fixed concentrations of desloratadine at various concentrations. (d) Concentration–effect curves of desloratadine in the presence of various fixed concentrations of simvastatin. (c) Combination index (CI) – fractional myotube death (fa) plot. CI = 1 indicates additivity (no interaction). The points above 1 indicate antagonism and those below indicate synergism. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Mentions: We hypothesized that the DDIs identified previously may result from, at least in part, the inhibition of OATP1B1/1B3 that leads to impaired hepatic uptake and compromised hepatic clearance. We first evaluated the potential of the drugs, as well as their pharmacologically active metabolites, to inhibit the active uptake of β‐estradiol 17‐β‐D‐glucuronide (E217βDG) in cryopreserved rat hepatocytes. E217βDG is a relatively specific substrate of OATP1B2, a functional homolog of human OATP1B1/1B3 with very similar substrate specificity.17, 20 At 100 μM, simvastatin acid, omeprazole, alprazolam, desloratadine (the active metabolite of loratadine), simvastatin, tegaserod, ropinirole, loratadine, and promethazine inhibited E217βDG uptake by 103.3 ± 0.5%, 60.1 ± 4.8%, 54.5 ± 0.3%, 44.9 ± 14.2%, 36.3 ± 6.0%, 24.6 ± 15.3%, 23.7 ± 2.7%, 18.1 ± 10.9%, and 17.7 ± 7.7%, respectively. We then determined the inhibitory potencies of the drugs showing ≥45% inhibition. The IC50s (95% CI) of simvastatin acid, omeprazole, alprazolam, and desloratadine were 4.3 μM (3.5, 5.3), 84.3 μM (49.8, 142.9), 99.5 μM (79.5, 124.6), and 140.5 (111.4, 177.1) μM, respectively (inhibition curves are shown in Supplementary Figure1).

View Article: PubMed Central - PubMed

ABSTRACT

Myopathy is a group of muscle diseases that can be induced or exacerbated by drug–drug interactions (DDIs). We sought to identify clinically important myopathic DDIs and elucidate their underlying mechanisms. Five DDIs were found to increase the risk of myopathy based on analysis of observational data from the Indiana Network of Patient Care. Loratadine interacted with simvastatin (relative risk 95% confidence interval [CI] = [1.39, 2.06]), alprazolam (1.50, 2.31), ropinirole (2.06, 5.00), and omeprazole (1.15, 1.38). Promethazine interacted with tegaserod (1.94, 4.64). In vitro investigation showed that these DDIs were unlikely to result from inhibition of drug metabolism by CYP450 enzymes or from inhibition of hepatic uptake via the membrane transporter OATP1B1/1B3. However, we did observe in vitro synergistic myotoxicity of simvastatin and desloratadine, suggesting a role in loratadine–simvastatin interaction. This interaction was epidemiologically confirmed (odds ratio 95% CI = [2.02, 3.65]) using the data from the US Food and Drug Administration Adverse Event Reporting System.

No MeSH data available.