Evaluation of the pharmacokinetic drug-drug interaction potential of iohexol, a renal filtration marker
PURPOSE: Carboplatin dose is calculated based on kidney function, commonly estimated with imperfect creatinine-based formulae. Iohexol is used to measure glomerular filtration rate (GFR) and allows calculation of a more appropriate carboplatin dose. To address potential concerns that iohexol administered during a course of chemotherapy impacts that therapy, we performed in vitro and in vivo pharmacokinetic drug-drug interaction evaluations of iohexol.
METHODS: Carboplatin was administered IV to female mice at 60 mg/kg with or without iohexol at 300 mg/kg. Plasma ultrafiltrate, kidney and bone marrow platinum was quantitated by atomic absorption spectrophotometry. Paclitaxel microsomal and gemcitabine cytosolic metabolism as well as metabolism of CYP and UGT probes was assessed with and without iohexol at 300 µg/mL by LC-MS/MS.
RESULTS: In vivo carboplatin exposure was not significantly affected by iohexol co-administration (platinum AUC combination vs alone: plasma ultrafiltrate 1,791 vs 1920 µg/mL min; kidney 8367 vs 9757 µg/g min; bone marrow 12.7 vs 12.7 µg/mg-protein min). Paclitaxel microsomal metabolism was not impacted (combination vs alone: 6-α-OH-paclitaxel 38.3 versus 39.4 ng/mL/60 min; 3-p-OH-paclitaxel 26.2 versus 27.7 ng/mL/60 min). Gemcitabine human cytosolic elimination was not impacted (AUC combination vs gemcitabine alone: dFdU 24.1 versus 23.7 µg/mL/30 min). Iohexol displayed no relevant inhibition of the CYP and UGT enzymes in human liver microsomes.
CONCLUSIONS: Iohexol is unlikely to affect the clinical pharmacokinetics of carboplatin, paclitaxel, gemcitabine, or other agents used in combination with carboplatin treatment. Measuring GFR with iohexol to better dose carboplatin is unlikely to alter the safety or efficacy of chemotherapy through pharmacokinetic drug-drug interactions.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:86 |
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| Enthalten in: |
Cancer chemotherapy and pharmacology - 86(2020), 4 vom: 13. Okt., Seite 535-545 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Joshi, Anand [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 20.05.2021 Date Revised 07.12.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s00280-020-04145-6 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM31520298X |
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| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Joshi, Anand |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Evaluation of the pharmacokinetic drug-drug interaction potential of iohexol, a renal filtration marker |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 20.05.2021 | ||
| 500 | |a Date Revised 07.12.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a PURPOSE: Carboplatin dose is calculated based on kidney function, commonly estimated with imperfect creatinine-based formulae. Iohexol is used to measure glomerular filtration rate (GFR) and allows calculation of a more appropriate carboplatin dose. To address potential concerns that iohexol administered during a course of chemotherapy impacts that therapy, we performed in vitro and in vivo pharmacokinetic drug-drug interaction evaluations of iohexol | ||
| 520 | |a METHODS: Carboplatin was administered IV to female mice at 60 mg/kg with or without iohexol at 300 mg/kg. Plasma ultrafiltrate, kidney and bone marrow platinum was quantitated by atomic absorption spectrophotometry. Paclitaxel microsomal and gemcitabine cytosolic metabolism as well as metabolism of CYP and UGT probes was assessed with and without iohexol at 300 µg/mL by LC-MS/MS | ||
| 520 | |a RESULTS: In vivo carboplatin exposure was not significantly affected by iohexol co-administration (platinum AUC combination vs alone: plasma ultrafiltrate 1,791 vs 1920 µg/mL min; kidney 8367 vs 9757 µg/g min; bone marrow 12.7 vs 12.7 µg/mg-protein min). Paclitaxel microsomal metabolism was not impacted (combination vs alone: 6-α-OH-paclitaxel 38.3 versus 39.4 ng/mL/60 min; 3-p-OH-paclitaxel 26.2 versus 27.7 ng/mL/60 min). Gemcitabine human cytosolic elimination was not impacted (AUC combination vs gemcitabine alone: dFdU 24.1 versus 23.7 µg/mL/30 min). Iohexol displayed no relevant inhibition of the CYP and UGT enzymes in human liver microsomes | ||
| 520 | |a CONCLUSIONS: Iohexol is unlikely to affect the clinical pharmacokinetics of carboplatin, paclitaxel, gemcitabine, or other agents used in combination with carboplatin treatment. Measuring GFR with iohexol to better dose carboplatin is unlikely to alter the safety or efficacy of chemotherapy through pharmacokinetic drug-drug interactions | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Carboplatin | |
| 650 | 4 | |a Drug-drug interaction | |
| 650 | 4 | |a Gemcitabine | |
| 650 | 4 | |a Glomerular filtration rate | |
| 650 | 4 | |a Iohexol | |
| 650 | 4 | |a Mouse | |
| 650 | 4 | |a Optimal dosing | |
| 650 | 4 | |a Paclitaxel | |
| 650 | 4 | |a Pharmacokinetics | |
| 650 | 4 | |a Renal function | |
| 650 | 7 | |a Contrast Media |2 NLM | |
| 650 | 7 | |a Deoxycytidine |2 NLM | |
| 650 | 7 | |a 0W860991D6 |2 NLM | |
| 650 | 7 | |a Iohexol |2 NLM | |
| 650 | 7 | |a 4419T9MX03 |2 NLM | |
| 650 | 7 | |a Cytochrome P-450 Enzyme System |2 NLM | |
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| 650 | 7 | |a Creatinine |2 NLM | |
| 650 | 7 | |a AYI8EX34EU |2 NLM | |
| 650 | 7 | |a Carboplatin |2 NLM | |
| 650 | 7 | |a BG3F62OND5 |2 NLM | |
| 650 | 7 | |a Glucuronosyltransferase |2 NLM | |
| 650 | 7 | |a EC 2.4.1.17 |2 NLM | |
| 650 | 7 | |a Paclitaxel |2 NLM | |
| 650 | 7 | |a P88XT4IS4D |2 NLM | |
| 650 | 7 | |a Gemcitabine |2 NLM | |
| 700 | 1 | |a Guo, Jianxia |e verfasserin |4 aut | |
| 700 | 1 | |a Holleran, Julianne L |e verfasserin |4 aut | |
| 700 | 1 | |a Kiesel, Brian |e verfasserin |4 aut | |
| 700 | 1 | |a Taylor, Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Christner, Susan |e verfasserin |4 aut | |
| 700 | 1 | |a Parise, Robert A |e verfasserin |4 aut | |
| 700 | 1 | |a Miller, Brian M |e verfasserin |4 aut | |
| 700 | 1 | |a Ivy, S Percy |e verfasserin |4 aut | |
| 700 | 1 | |a Chu, Edward |e verfasserin |4 aut | |
| 700 | 1 | |a Venkataramanan, Raman |e verfasserin |4 aut | |
| 700 | 1 | |a Beumer, Jan H |e verfasserin |4 aut | |
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| 773 | 1 | 8 | |g volume:86 |g year:2020 |g number:4 |g day:13 |g month:10 |g pages:535-545 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1007/s00280-020-04145-6 |3 Volltext |
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