Open Access

Drug-drug-gene interactions as mediators of adverse drug reactions to diclofenac and statins: a case report and literature review

Nada Božina
Nada Božina
, 
Lana Ganoci
Lana Ganoci
, 
Livija Simičević
Livija Simičević
, 
Katarina Gvozdanović
Katarina Gvozdanović
, 
Iva Klarica Domjanović
Iva Klarica Domjanović
, 
Margareta Fistrek Prlić
Margareta Fistrek Prlić
, 
Tena Križ
Tena Križ
, 
Ana Borić Bilušić
Ana Borić Bilušić
, 
Mario Laganović
Mario Laganović
 and 
Tamara Božina
Tamara Božina
   | Jun 28, 2021
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Article Category: Case report / Review
Published Online: Jun 28, 2021
Page range: 114 - 128
Received: Apr 01, 2021
Accepted: May 01, 2021
DOI: https://doi.org/10.2478/aiht-2021-72-3549
© 2021 Nada Božina, Lana Ganoci, Livija Simičević, Katarina Gvozdanović, Iva Klarica Domjanović, Margareta Fistrek Prlić, Tena Križ, Ana Borić Bilušić, Mario Laganović, and Tamara Božina, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Figure 1

The timeline of the first hospitalisation with all pharmacotherapy and laboratory data
The timeline of the first hospitalisation with all pharmacotherapy and laboratory data

Figure 2

The timeline of the second hospitalisation with all pharmacotherapy and laboratory data
The timeline of the second hospitalisation with all pharmacotherapy and laboratory data

Figure 3

Diclofenac transport and metabolism (adopted from PharmGKB pathway images at https://www.pharmgkb.org/pathway/PA166163705 under the Creative Commons BY-SA 4.0 license)
Diclofenac transport and metabolism (adopted from PharmGKB pathway images at https://www.pharmgkb.org/pathway/PA166163705 under the Creative Commons BY-SA 4.0 license)

Figure 4

Major statins transport and metabolism pathways (own illustration)
Major statins transport and metabolism pathways (own illustration)

Pharmacogenetic profile of our patient and related pharmacotherapy

Gene-allele Genotype Phenotype Drug-substrate Drug-inhibitor
CYP2C9 *2, *3 *1/*3 intermediate metaboliser - IM diclofenac sulphamethoxazole trimethoprim atorvastatin fenofibrate simvastatin sulphamethoxazole
CYP2C19 *2, *17 *1/*1 normal metaboliser - NM diclofenac pantoprazole propranolol pantoprazole atorvastatin
CYP2D6 *3, *4, *5, *6, *41, xN *1/*4 intermediate metaboliser - IM propranolol atorvastatin propranolol
CYP3A4 *22 *1/*1 normal metaboliser - NM atorvastatin diclofenac pantoprazole propranolol prednisone simvastatin diclofenac pantoprazole
CYP3A5 *3 *3/*3 non-expresser atorvastatin propranolol simvastatin
UGT1A1 *28 *1/*28 intermediate enzyme activity atorvastatin furosemide simvastatin atorvastatin pantoprazole
UGT1A4 *2 (70C>A) *1/*1 normal enzyme activity atorvastatin
UGT1A4 *3 (142T>G) *1/*3 intermediate enzyme activity atorvastatin fenofibrate
UGT1A9 (-2152 C>T) C/C normal enzyme activity fenofibrate atorvastatin fenofibrate
UGT1A9 (-275 T>A ) T/T normal enzyme activity fenofibrate atorvastatin fenofibrate
UGT2B7 -161C>T T/T substrate depending low/high enzyme activity atorvastatin diclofenac propranolol simvastatin fenofibrate
ABCB1 (MDR1) 2677G>T/A ABCB1 (MDR1) 3435C>T G/G T/T decreased transporter function atorvastatin pantoprazole prednisone propranolol simvastatin atorvastatin ceftriaxone furosemide pantoprazole
ABCC2 (MRP2) -24C>T ABCC2 (MRP2) 1249G>A C/C G/G normal transporter function atorvastatin ceftriaxone diclofenac simvastatin furosemide
ABCG2 421C>A C/A decreased transporter function atorvastatin ceftriaxone diclofenac fenofibrate pantoprazole furosemide pantoprazole
SLCO1B1 *5 *1A/*5 decreased transporter function atorvastatin diclofenac simvastatin atorvastatin diclofenac fenofibrate
eISSN:
1848-6312
Languages:
English, Slovenian
Publication timeframe:
4 times per year
Journal Subjects:
Medicine, Basic Medical Science, other
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