Tobacco, cannabis, and liquorice: Hidden players altering albendazole metabolism in patients with hepatic alveolar echinococcosis.

Alveolar echinococcosis (AE) due to the tumour-like hepatic development of the metacestode Echinococcus (E.) multilocularis is lethal if untreated. AE is highly prevalent in Western China[1]Wen H. Vuitton L. Tuxun T. Li J. Vuitton D.A. Zhang W. et al.Echinococcosis: advances in the 21th century.Clin Microbiol Rev. 2019; 32 (e00075-10)Crossref PubMed Scopus (262) Google Scholar,[2]Vuitton D.A. Bresson-Hadni S. Alveolar echinococcosis: evaluation of therapeutic strategies.Expert Opin Orphan Drugs. 2014; 2: 67-86Crossref Scopus (31) Google Scholar and its incidence is increasing in nearly all European countries.[1]Wen H. Vuitton L. Tuxun T. Li J. Vuitton D.A. Zhang W. et al.Echinococcosis: advances in the 21th century.Clin Microbiol Rev. 2019; 32 (e00075-10)Crossref PubMed Scopus (262) Google Scholar,[2]Vuitton D.A. Bresson-Hadni S. Alveolar echinococcosis: evaluation of therapeutic strategies.Expert Opin Orphan Drugs. 2014; 2: 67-86Crossref Scopus (31) Google Scholar Complete surgical resection (including liver transplantation or ex vivo hepatic resection and auto-transplantation in life-threatening cases) is the treatment gold-standard, feasible in one-third of patients.1Wen H. Vuitton L. Tuxun T. Li J. Vuitton D.A. Zhang W. et al.Echinococcosis: advances in the 21th century.Clin Microbiol Rev. 2019; 32 (e00075-10)Crossref PubMed Scopus (262) Google Scholar, 2Vuitton D.A. Bresson-Hadni S. Alveolar echinococcosis: evaluation of therapeutic strategies.Expert Opin Orphan Drugs. 2014; 2: 67-86Crossref Scopus (31) Google Scholar, 3Brunetti E. Kern P. Vuitton D.A. Writing panel for the WHO-IWGEExpert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.Acta Tropica. 2010; 114: 1-16Crossref PubMed Scopus (1133) Google Scholar, 4Aji T. Dong J.-H. Shao Y.-M. Zhao J.M. Li T. Tuxun T. et al.Ex vivo liver resection and auto transplantation as alternative to allo transplantation for end-stage hepatic alveolar echinococcosis.J Hepatol. 2018; 69: 1037-1046Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar The parasitostatic drug albendazole (ABZ) is administered either for 2 years after hepatectomy or lifelong in inoperable cases.1Wen H. Vuitton L. Tuxun T. Li J. Vuitton D.A. Zhang W. et al.Echinococcosis: advances in the 21th century.Clin Microbiol Rev. 2019; 32 (e00075-10)Crossref PubMed Scopus (262) Google Scholar, 2Vuitton D.A. Bresson-Hadni S. Alveolar echinococcosis: evaluation of therapeutic strategies.Expert Opin Orphan Drugs. 2014; 2: 67-86Crossref Scopus (31) Google Scholar, 3Brunetti E. Kern P. Vuitton D.A. Writing panel for the WHO-IWGEExpert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.Acta Tropica. 2010; 114: 1-16Crossref PubMed Scopus (1133) Google Scholar ABZ is a high-clearance inactive pro-drug; its liver metabolism is primarily through cytochrome P450 (CYP) 1A2 and CYP3A4[5]Pawluk S.A. Roels C.A. Wilby K.J. Ensom M.H. A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole.Clin Pharmacokinet. 2015; 54: 371-383Crossref PubMed Scopus (33) Google Scholar into the active form ABZ-sulfoxide (ASOX) then into non-active ABZ sulfone.[2]Vuitton D.A. Bresson-Hadni S. Alveolar echinococcosis: evaluation of therapeutic strategies.Expert Opin Orphan Drugs. 2014; 2: 67-86Crossref Scopus (31) Google Scholar,[5]Pawluk S.A. Roels C.A. Wilby K.J. Ensom M.H. A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole.Clin Pharmacokinet. 2015; 54: 371-383Crossref PubMed Scopus (33) Google Scholar There are considerable inter-individual variations and no correlation between ABZ dosage and ASOX plasma concentration. Based on ASOX plasma levels (recommended range: 1 to 3 μmol/L, 4 hours after morning drug intake) therapeutic drug monitoring (TDM) allows dose adjustments for higher efficacy and less hepatic toxicity.[2]Vuitton D.A. Bresson-Hadni S. Alveolar echinococcosis: evaluation of therapeutic strategies.Expert Opin Orphan Drugs. 2014; 2: 67-86Crossref Scopus (31) Google Scholar We alert readers to the risk that lifestyle habits can interfere with ABZ metabolism. Case 1 (Fig. 1A-C): A 23-year-old woman was diagnosed in 1993 with two asymptomatic AE lesions invading hepatic veins and making curative surgery impossible. During 21-years follow-up the lesions remained stable under ABZ 400 mg b.i.d. with optimal ASOX plasma levels. In 2014, low ASOX levels were observed. There were neither co-medications nor poor adherence to treatment. ABZ dosage was increased to 600 mg b.i.d. but ASOX levels remained inexplicably low for 2 years. In 2016 MRI detected microcysts newly appeared between the two unchanged initial lesions. The patient eventually mentioned regular cannabis consumption since 2014. Cannabis interruption was rapidly followed by increased ASOX levels and stable lesions. Case 2: A 51-year-old man was diagnosed with AE in 2009. He was a heavy smoker (45 packs a year). Under ABZ 400mg b.i.d., ASOX levels were constantly low (<1 μmol/L) and dosage was increased under TDM. Finally, 700 mg b.i.d. were necessary to reach the recommended ASOX levels. In 2017, transient tobacco consumption reduction led to increased ASOX levels (4.02 μmol/L) without any clinical or biological adverse events. ABZ dosage was kept unchanged as the patient went back to his previous heavy consumption rapidly, with plasma ASOX levels similar to those observed previously and stable AE lesions. Case 3 (Fig. 1D-F): A 64-year-old woman was diagnosed with AE in 2016. Under ABZ 400 mg b.i.d., ASOX levels were above the therapeutic range, leading to dose reduction. Under ABZ 200mg b.i.d., ASOX levels remained constantly high, above 3 μmol/L but without drug adverse effect. There was no co-medication. In 2019, regular liquorice ingestion through a popular French non-alcoholic drink (Antésite®) was eventually reported by the patient (1 to 1.5 L/day) and she was asked to stop. Two weeks later, ASOX levels were within the therapeutic range. Interestingly, this exposure to high ASOX levels for 2 years led to an excellent control of AE: the initially positive Em18 ELISA serology regularly decreased to become negative in October 2018 and in February 2019 PET showed a complete disappearance of the lesion metabolic activity. Cytochrome P450 inducers (ritonavir, phenytoin, phenobarbital, or carbamazepine) are associated with low ASOX levels; conversely, inhibitors such as cimetidine may increase exposure to the active drug.5Pawluk S.A. Roels C.A. Wilby K.J. Ensom M.H. A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole.Clin Pharmacokinet. 2015; 54: 371-383Crossref PubMed Scopus (33) Google Scholar, 6Wen H. New R.R. Muhmut M. Wang J.H. Wang Y.H. Zhang J.H. et al.Pharmacology and efficacy of liposome-entrapped albendazole in experimental secondary alveolar echinococcosis and effect of co-administration with cimetidine.Parasitology. 1996; 113: 111-121Crossref PubMed Google Scholar, 7Nagy J. Schipper H.G. Koopmans R.P. Butter J.J. Van Boxtel C.J. Kager P.A. Effect of grapefruit juice or cimetidine coadministration on albendazole bioavailability.Am J Trop Med Hyg. 2002; 66: 260-263Crossref PubMed Scopus (61) Google Scholar Our observations demonstrate that life habits may also interfere with ABZ. Both cannabis and tobacco smoking are known to induce CYP1A2,[8]Anderson G.D. Chan L.-N. Pharmacokinetic drug interactions with tobacco, cannabinoids and smoking cessation products.Clin Pharmacokinet. 2016; 55: 1353-1368Crossref PubMed Scopus (81) Google Scholar which was responsible for low ASOX levels, a situation which led to AE progression in Case 1. In Case 2, tobacco consumption was known at time of diagnosis; TDM was very helpful to gradually increase ABZ dosage to a higher level than usually recommended.[2]Vuitton D.A. Bresson-Hadni S. Alveolar echinococcosis: evaluation of therapeutic strategies.Expert Opin Orphan Drugs. 2014; 2: 67-86Crossref Scopus (31) Google Scholar,[3]Brunetti E. Kern P. Vuitton D.A. Writing panel for the WHO-IWGEExpert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.Acta Tropica. 2010; 114: 1-16Crossref PubMed Scopus (1133) Google Scholar Then, the patient remained asymptomatic for 10 years. On the contrary, in Case 3 we observed constantly high and unexplained ASOX levels. Querying the patient's life habits allowed us to identify liquorice consumption as the cause of the pharmacological disturbance. Liquorice's main constituent, glycyrrhizic acid and its gut-derived metabolite 18β-glycyrrhetinic acid inhibit several CYP450 enzymes.[9]Li G. Simmler C. Chen L. Nikolic D. Chen S.N. Pauli G.F. et al.Cytochrome P450 inhibition by three licorice species and fourteen licorice constituants.Eur J Pharm Sci. 2017; 109: 182-190Crossref PubMed Scopus (30) Google Scholar Fortunately, no ABZ toxicity was observed in our patient; we may even suggest that this metabolic inhibition contributed to the excellent ABZ efficacy on the lesions. Such an interaction with a trivial beverage was previously reported in healthy volunteers with grapefruit juice and attributed to interference at CYP3A4 enzyme levels in the intestinal mucosa.[7]Nagy J. Schipper H.G. Koopmans R.P. Butter J.J. Van Boxtel C.J. Kager P.A. Effect of grapefruit juice or cimetidine coadministration on albendazole bioavailability.Am J Trop Med Hyg. 2002; 66: 260-263Crossref PubMed Scopus (61) Google Scholar In conclusion, life habits such as tobacco, cannabis, or liquorice consumption may interfere with ABZ metabolism as strongly as the well-known inducing or inhibiting drugs. This stresses the usefulness of ASOX TDM in patients with AE under ABZ. Physicians in charge of patients with cystic echinococcosis (CE) should also be aware of such interferences. Systematic and regular questioning of patients on their life habits at presentation and during follow-up may be highly beneficial. This work is supported by the French National Agency for Public Health (Santé Publique France) through the funding for the French National Reference Center on Echinococcosis. All authors contributed to this work and approved the final version of the manuscript. The 3 alveolar echinococcosis (AE) patients have given informed consent to be included in the French AE registry, FrancEchino, and have accepted the scientific use of their medical data. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. Download .pdf (.25 MB) Help with pdf files disclosures.pdf