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Effects of Metformin and Furosemide on Rosuvastatin Pharmacokinetics in Healthy Volunteers: Implications for Their Use as Probe Drugs in a Transporter Cocktail.
Eur J Drug Metab Pharmacokinet. 2018 Feb; 43(1):69-80.EJ

Abstract

BACKGROUND

In a recently described probe drug cocktail for clinically relevant drug transporters containing digoxin, furosemide, metformin and rosuvastatin, mutual interactions were essentially absent except for increases in the systemic exposure of rosuvastatin. To optimize the cocktail, we further examined the dose dependence of the effects of metformin and furosemide on rosuvastatin pharmacokinetics.

METHODS

This was a randomized, open label, single center, six-treatment, six-period, six-sequence crossover trial. Eighteen healthy male subjects received 10 mg rosuvastatin as reference treatment and, as test treatments, 10 mg rosuvastatin combined with 10, 50 or 500 mg metformin (T1, T2 and T3) or with 1 or 5 mg furosemide (T4 and T5). Primary pharmacokinetic endpoints were rosuvastatin C max (maximum plasma concentration) and AUC0-tz (area under the plasma concentration-time curve from time zero to the last quantifiable concentration).

RESULTS

The relative bioavailability of rosuvastatin was essentially unchanged when administered with metformin in T1 and T2, but in T3 it increased to 152% for AUC0-tz (90% CI 135-171%) and 154% for C max (90% CI 132-180%). Coadministration with furosemide did not change rosuvastatin relative bioavailability in T4, but in T5 it increased slightly to 116% for AUC0-tz (90% CI 102-132%) and 118% for C max (90% CI 98-142%).

CONCLUSION

The increased systemic exposure of rosuvastatin when administered as part of the proposed transporter cocktail is most likely attributable to metformin and only to a minor degree to furosemide. Reduction of the doses of metformin and furosemide is expected to eliminate the previously described interaction. EudraCT no. 2015-003052-46, ClinicalTrials.gov identifier NCT02574845.

Authors+Show Affiliations

Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany. Peter.Stopfer@boehringer-ingelheim.com.Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co. Ltd., Chuo-ku, Kobe, Japan.Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT, 06877, USA.Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.

Pub Type(s)

Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

28685495

Citation

Stopfer, Peter, et al. "Effects of Metformin and Furosemide On Rosuvastatin Pharmacokinetics in Healthy Volunteers: Implications for Their Use as Probe Drugs in a Transporter Cocktail." European Journal of Drug Metabolism and Pharmacokinetics, vol. 43, no. 1, 2018, pp. 69-80.
Stopfer P, Giessmann T, Hohl K, et al. Effects of Metformin and Furosemide on Rosuvastatin Pharmacokinetics in Healthy Volunteers: Implications for Their Use as Probe Drugs in a Transporter Cocktail. Eur J Drug Metab Pharmacokinet. 2018;43(1):69-80.
Stopfer, P., Giessmann, T., Hohl, K., Sharma, A., Ishiguro, N., Taub, M. E., Jungnik, A., Gansser, D., Ebner, T., & Müller, F. (2018). Effects of Metformin and Furosemide on Rosuvastatin Pharmacokinetics in Healthy Volunteers: Implications for Their Use as Probe Drugs in a Transporter Cocktail. European Journal of Drug Metabolism and Pharmacokinetics, 43(1), 69-80. https://doi.org/10.1007/s13318-017-0427-9
Stopfer P, et al. Effects of Metformin and Furosemide On Rosuvastatin Pharmacokinetics in Healthy Volunteers: Implications for Their Use as Probe Drugs in a Transporter Cocktail. Eur J Drug Metab Pharmacokinet. 2018;43(1):69-80. PubMed PMID: 28685495.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of Metformin and Furosemide on Rosuvastatin Pharmacokinetics in Healthy Volunteers: Implications for Their Use as Probe Drugs in a Transporter Cocktail. AU - Stopfer,Peter, AU - Giessmann,Thomas, AU - Hohl,Kathrin, AU - Sharma,Ashish, AU - Ishiguro,Naoki, AU - Taub,Mitchell E, AU - Jungnik,Arvid, AU - Gansser,Dietmar, AU - Ebner,Thomas, AU - Müller,Fabian, PY - 2017/7/8/pubmed PY - 2018/8/14/medline PY - 2017/7/8/entrez SP - 69 EP - 80 JF - European journal of drug metabolism and pharmacokinetics JO - Eur J Drug Metab Pharmacokinet VL - 43 IS - 1 N2 - BACKGROUND: In a recently described probe drug cocktail for clinically relevant drug transporters containing digoxin, furosemide, metformin and rosuvastatin, mutual interactions were essentially absent except for increases in the systemic exposure of rosuvastatin. To optimize the cocktail, we further examined the dose dependence of the effects of metformin and furosemide on rosuvastatin pharmacokinetics. METHODS: This was a randomized, open label, single center, six-treatment, six-period, six-sequence crossover trial. Eighteen healthy male subjects received 10 mg rosuvastatin as reference treatment and, as test treatments, 10 mg rosuvastatin combined with 10, 50 or 500 mg metformin (T1, T2 and T3) or with 1 or 5 mg furosemide (T4 and T5). Primary pharmacokinetic endpoints were rosuvastatin C max (maximum plasma concentration) and AUC0-tz (area under the plasma concentration-time curve from time zero to the last quantifiable concentration). RESULTS: The relative bioavailability of rosuvastatin was essentially unchanged when administered with metformin in T1 and T2, but in T3 it increased to 152% for AUC0-tz (90% CI 135-171%) and 154% for C max (90% CI 132-180%). Coadministration with furosemide did not change rosuvastatin relative bioavailability in T4, but in T5 it increased slightly to 116% for AUC0-tz (90% CI 102-132%) and 118% for C max (90% CI 98-142%). CONCLUSION: The increased systemic exposure of rosuvastatin when administered as part of the proposed transporter cocktail is most likely attributable to metformin and only to a minor degree to furosemide. Reduction of the doses of metformin and furosemide is expected to eliminate the previously described interaction. EudraCT no. 2015-003052-46, ClinicalTrials.gov identifier NCT02574845. SN - 2107-0180 UR - https://www.unboundmedicine.com/medline/citation/28685495/Effects_of_Metformin_and_Furosemide_on_Rosuvastatin_Pharmacokinetics_in_Healthy_Volunteers:_Implications_for_Their_Use_as_Probe_Drugs_in_a_Transporter_Cocktail_ L2 - https://dx.doi.org/10.1007/s13318-017-0427-9 DB - PRIME DP - Unbound Medicine ER -