title: Hepatic drug interaction between tacrolimus and lansoprazole in a bone marrow transplant patient receiving voriconazole and harboring CYP2C19 and CYP3A5 heterozygous mutations.
abstract: BACKGROUND
  A drug interaction between oral tacrolimus (TAC) and lansoprazole (LAN) has been reported in patients with CYP2C19 hetero/homozygous mutations and the CYP3A5 *3/*3 genotype. A PubMed search (implemented March 16, 2011) using search terms drug interaction, tacrolimus, and lansoprazole failed to identify drug interactions in CYP3A5 extensive metabolizers and parenterally administered TAC.
  
  
  OBJECTIVE
  The purpose of this study was to report a case of drug interaction between intravenously administered TAC and LAN in a patient being treated with voriconazole (VCZ) and harboring CYP2C19 and CYP3A5 heterozygous mutations.
  
  
  METHODS
  An 18-year-old Japanese man weighing 53 kg with an anaplastic large cell lymphoma received continuous IV administration of TAC as post-transplantation prophylaxis against graft-versus-host disease (GVHD) after an allogeneic bone marrow transplantation (BMT). He began receiving IV LAN 60 mg/d and VCZ 400 mg/d initiated the day before BMT. His blood TAC concentrations were within the range of 9-16 ng/mL from post-BMT day 5 to 26. The engraftment of the donor's hematopoietic cells was observed on day 17. The LAN dose was reduced to 15 mg/d PO on day 26, and the blood TAC concentration subsequently decreased to 6.6 ng/mL, with GVHD-related symptoms emerging on day 28. Consequently, the plasma VCZ concentration also decreased from 5.0 ng/mL to 2.5 ng/mL after reducing the LAN dose. VCZ was switched to liposomal amphotericin B on day 48. Thereafter, the blood TAC concentration decreased to 4.4 ng/mL on day 51. Ultimately, the patient died on day 77 because of the recurrence and progression of lymphoma. Other drugs taken were acyclovir, ursodeoxycholic acid, cefepime, meropenem, vancomycin, lenograstim, and dopamine hydrochloride. The genotyping analyses using the pre-BMT and post-engraftment (day 33) samples indicated that both were CYP2C19 *1/*2, CYP3A5 *1/*3 and CYP2C9 *1/*1. The calculated Drug Interaction Probability Score between TAC and LAN was 6, indicating a probable interaction. TAC and VCZ concentrations were measured by an affinity column-mediated immunometric assay and HPLC, respectively. Mutant alleles were examined using the multiplex extension of unlabeled oligonucleotide primers with fluorescently labeled dideoxynucleoside triphosphates.
  
  
  CONCLUSIONS
  In a BMT patient with CYP2C19 and CYP3A5 heterozygous mutations, blood TAC concentration decreased after reducing the LAN dose, which appeared to be caused by a reduction in plasma VCZ concentration.
authors.affiliation: Department of Pharmacy, Mie University Hospital, Tsu, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Monma
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fujieda
authors.forename: Kaname
authors.initials: K
authors.lastname: Nakatani
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Katayama
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okuda
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000293:Adolescent; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D016026:Bone Marrow Transplantation / Q000379:methods; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D007262:Infusions, Intravenous; D064747:Lansoprazole; D008099:Liver / Q000378:metabolism; D008297:Male; D009154:Mutation; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014230:Triazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D065819:Voriconazole
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D011743:Pyrimidines; D014230:Triazoles; D064747:Lansoprazole; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C510164:CYP3A5 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065819:Voriconazole; D016559:Tacrolimus