Orange juice decreases the oral bioavailability of ivermectin in healthy volunteers

Vanapalli, Sreenivasa R.; Chen, Y.; Ellingrod, V. L.; Kitzman, Dennis; Lee, Y.; Hohl, R. J.; Fleckenstein, Lawrence

doi:10.1016/s0009-9236(03)90702-8

Cited by 16 publications

(12 citation statements)

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“…We included rifampicin, a dual CYP3A4/P-gp inducer 49 to validate the results, evaluate changes in the CSF concentration and better understand the potential routes of manipulation of detoxification enzymes/transporters in the mosquito. Yet, Rifampicin mediated CYP 3A4/P-gp induction led to a marked reduction in systemic ivermectin exposure, possibly due to reduced intestinal absorption and/or pre-systemic metabolism; Although there is no evidence that ivermectin is a substrate of Organic Anion-Transporting Polypeptides (OATPs) in hepatic tissue or the intestinal epithelium, decreased bioavailability when co-administered with orange juice suggests this could occur 68 , 69 . If this was the case, inhibition of OATPs mediated uptake by rifampicin 70 could have also contributed to the reduced ivermectin absorption seen in our rifampicin pre-treated mini-pigs.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae

Chaccour

Hammann

Alustiza

et al. 2017

Sci Rep

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Mass administration of endectocides, drugs that kill blood-feeding arthropods, has been proposed as a complementary strategy to reduce malaria transmission. Ivermectin is one of the leading candidates given its excellent safety profile. Here we provide proof that the effect of ivermectin can be boosted at two different levels by drugs inhibiting the cytochrome or ABC transporter in the mammal host and the target mosquitoes. Using a mini-pig model, we show that drug-mediated cytochrome P450/ABC transporter inhibition results in a 3-fold increase in the time ivermectin remains above mosquito-killing concentrations. In contrast, P450/ABC transporter induction with rifampicin markedly impaired ivermectin absorption. The same ketoconazole-mediated cytochrome/ABC transporter inhibition also occurs outside the mammal host and enhances the mortality of Anopheles gambiae. This was proven by using the samples from the mini-pig experiments to conduct an ex-vivo synergistic bioassay by membrane-feeding Anopheles mosquitoes. Inhibiting the same cytochrome/xenobiotic pump complex in two different organisms to simultaneously boost the pharmacokinetic and pharmacodynamic activity of a drug is a novel concept that could be applied to other systems. Although the lack of a dose-response effect in the synergistic bioassay warrants further exploration, our study may have broad implications for the control of parasitic and vector-borne diseases.

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Section: Discussionmentioning

confidence: 99%

Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae

Chaccour

Hammann

Alustiza

et al. 2017

Sci Rep

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“…Orange juice decreased AUC (15.7 ng·d·ml ), possibly because fruit juices and constituents are potent inhibitors of certain drug transporters (14).…”

Section: Interactionsmentioning

confidence: 99%

“…A significant effect of gender was found in ivermectin pharmacokinetics in healthy volunteers orally treated with 150 μg/kg, with a lower total body Cl/F in males compared to females (see Table 1) (14).…”

Section: Eliminationmentioning

confidence: 99%

The Pharmacokinetics and Interactions of Ivermectin in Humans—A Mini-review

Canga

Sahagún

Diez

et al. 2008

AAPS J

315

238

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“…Although the total and weight-adjusted ivermectin doses were comparable between males and females in both dose groups, the higher estimated adipose weight of female rats resulted in a 3 to 4-fold dose of ivermectin per gram of fat. Ivermectin accumulates in adipose tissue 25 , this deep compartment affects systemic concentrations of the drug in subjects with different body composition and sex-based differences have been well described before 26,30 . In this experiment there was a direct relationship between the dose per gram of fat and the plasma levels reached at 1, 4 and 24 hours.…”

Section: Dose and Body Compositionmentioning

confidence: 99%

Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats

Chaccour

Abizanda

Irigoyen-Barrio

et al. 2020

Preprint

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Background: Ivermectin is a widely used antiparasitic drug with known efficacy against several single-strain RNA viruses. Recent data shows significant reduction of SARS-CoV-2 replication in vitro by ivermectin concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for other antiparasitics. Methods: An ethanol-based ivermectin formulation was administered once to 14 rats using a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into three target dosing groups, lower dose (80-90 mg/kg), higher dose (110-140 mg/kg) or ethanol vehicle only. A toxicology profile including behavioral and weight monitoring, full blood count, biochemistry, necropsy and histological examination of the lungs was conducted. The pharmacokinetic profile of ivermectin in plasma and lungs was determined in all animals. Results: There were no relevant changes in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose which was up to 11 grams/kg in some animals. There were no histological anomalies in the lungs of any rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher plasma concentrations than females in the same dosing group (mean Cmax 86.2 ng/ml vs 26.2 ng/ml in the lower dose group and 152 ng/ml vs 51.8 ng/ml in the higher dose group). All subjects had detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3 ng/g for high-dose male and 27.3 ng/g for low-dose females. Conclusion: nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats, additional experiments are required to assess the safety of this formulation in larger animals.

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Orange juice decreases the oral bioavailability of ivermectin in healthy volunteers

Abstract: Clinical Pharmacology & Therapeutics (2003) 73, P94–P94; doi:

Cited by 16 publications

References 0 publications

Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae

Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae

The Pharmacokinetics and Interactions of Ivermectin in Humans—A Mini-review

Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats

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