while drugs can cause acute rhabdomyolysis individually , they can also interact with other drugs by cytochrome p450 and p - glycoprotein mechanisms to bring on the syndrome.clinicians should evaluate drug interactions in patients taking two or more medications .
acute rhabdomyolysis ( ar ) is a clinical syndrome that occurs when the electrolytes and myoglobin that are released upon skeletal muscle damage enter into the circulation system .
there are several ways in which ar may occur , one of which is drugs ( fig . 
1etiology of acute rhabdomyolysis and its complications etiology of acute rhabdomyolysis and its complications a comprehensive study was carried out in 2011 using 20042009 data of the us food and drug administration ( fda ) to reveal which drugs may be associated with rhabdomyloysis .
the etiologies of 16,435 drug - induced cases of rhabdomyloysis involved hmg - coa reductase inhibitors or statins ( n  =  4325 , 26.3  % ) as the first suspect .
a total of 100 cases were reported for diclofenac and 99 for omeprazole , a proton pump inhibitor , while there were no reports of cases associated with pantoprazole .
the cases of drug - induced rhabdomyolysis in previous literature were also associated with statins , and the frequency is similar to that reported in the abovementioned report . that said , drug interactions could not be assessed because the fda data did not include that level of systematic information .
the gastric side effects of non - steroidal anti - inflammatory drugs ( nsaids ) are well known , and their concomitant or subsequent combination with proton pump inhibitors is common . a review of adverse drug reactions , creatinine kinase elevations , and muscle events , including muscle weakness , myopathy , myositis , and polymyositis , analyzed such multiple drug regimens and found that the addition of pantoprazole to a treatment regimen was the cause of all muscle events , aside from myalgia .
a 45-year - old man was referred to hospital complaining of fatigue and extensive body pain .
his medical history included stress - induced headaches that had been present for almost the entire previous year , for which he began using diclofenac at 50  mg / day as the frequency of headaches had increased during the prior month .
he was referred to a physician for pyrosis , 1  week prior to presenting at the hospital , and was prescribed pantoprazole at 40  mg / day .
he started to experience pain in his leg muscles on the fourth day of the diclofenac and pantoprazole combination regimen and used two 50-mg doses of diclofenac to control the pain .
the muscle pain became more widespread on the fifth day , and the patient also developed fatigue .
an examination revealed a blood pressure of 120/80  mmhg and a pulse of 76  bpm , full and rhythmic .
muscular strength was good ; however , the patient complained of muscle tenderness upon palpation .
neurological and general system examinations were normal ; no abnormal findings were seen in an electrocardiogram ; and an abdomen ultrasound revealed no pathology , aside from an abdominal gas distention . a laboratory analysis revealed high levels of muscle destruction products , the foremost of which was creatinine kinase ( table  1 ) .
glucose , urea , creatinine , cholesterol levels , amylase , direct and indirect bilirubin , electrolytes , anti - streptolysin o , c - reactive protein , rheumatoid factor , and thyroid hormones were all within their normal ranges.table  1laboratory parameters of patientadmission7  days afterreference rangeglucose ( mg / dl)96n / a70105alp ( alkaline phosphatase ) ( iu / l)565164306sgpt ( iu / l)4512042sgot ( iu / l)8814534ck ( iu / l)31146724190creatinine ( mg / dl)0.760.670.751.25crp ( mg / dl)0.880.5905ldh ( iu / l)230168125220 
 alp alkaline phosphatase , ck creatine kinase , crp c - reactive protein , ldh lactate dehydrogenase , n / a not available , sgot serum glutamic oxaloacetic transaminase , sgpt serum glutamic pyruvic transaminase laboratory parameters of patient 
 alp alkaline phosphatase , ck creatine kinase , crp c - reactive protein , ldh lactate dehydrogenase , n / a not available , sgot serum glutamic oxaloacetic transaminase , sgpt serum glutamic pyruvic transaminase a cardiac pathology was excluded because the electrocardiographic assessments and cardiac sounds were normal , and because the patient did not describe any pain that would indicate an infarct , and test results and findings were stable on the following days .
ar was considered as a pre - diagnosis , as there was a chronologic alignment between the patient s clinical representation and the medications he used , and this was supported by the laboratory parameters .
both medications were discontinued and the patient was followed up for 1  week , during which no medical interventions were carried out , aside from a recommendation of general hydration .
the ar diagnosis was confirmed because his complaints disappeared , with his laboratory values returning to the normal range , a stable electrocardiogram , and other systemic examinations being found within normal ranges .
to date , among the cases involving nsaids , two cases were reported that include diclofenac - induced rhabdomyloysis [ 4 , 5 ] . the patient detailed in this study was referred with extensive pain and fatigue , and represents the third case in which rhabdomyloysis developed while using 100-mg / day diclofenac tablets .
the other two cases were induced by diclofenac alone , with no interaction with other drugs . of these , one patient was admitted with pain that increased after the patient took 200  mg of diclofenac within 2  days ( 50  mg tablet / twice a day ) for joint pain .
the other case involved a patient who used diclofenac to ease an acute exacerbation of gout .
the patient was referred to a physician on the 13th day of intramuscularly self - administered diclofenac at 75  mg per day for 6  days , followed by 75  mg orally three times a day for 7  days . unlike the previous case , this patient was referred to the hospital because of erythematous pruritic eruptions that developed on various parts of his body . while drugs can cause ar individually , they can also interact with other drugs to bring on the syndrome .
the cyp1 , cyp2 , and cyp3 gene families are overall responsible for drug metabolism , and the similarities between the amino acid sequences within a gene family are at least 40  % , although the level of similarity may increase to 85  % between subgroups . the genetic polymorphisms in these genes
alter the biotransformation of the drug . while fast metabolizers have increased enzyme activity , slow metabolizers show decreased enzyme activity . among these genes ,
theophylline , which is metabolized through this pathway , when used with erythromycin , returns to the cyp1a2 pathway and can not reach toxic concentrations [ 79 ] .
that said , to date , no such theory has been put forward for diclofenac and pantoprazole in the cyp enzyme system .
the fact that they are metabolized through the same subgroup ( 2c ) can be associated with a possible drug interaction .
this possibility of interaction between diclofenac and pantoprazole has been investigated in a randomized crossover trial of 24 subjects , and the results showed that the peak plasma concentrations of diclofenac are sustained in a stable range , and that diclofenac does not affect the pharmacokinetics of pantoprazole , meaning that this combination is completely safe .
however , the results of an in - vitro study using diclofenac as a substrate marker for human liver microsomes suggested the contrary . according to this study , proton pump inhibitors , the strongest one being pantoprazole , carry a strong potential for drug interaction by inhibiting the activity of cyp enzymes , and it was underlined that drug interactions are significantly more pronounced in weak metabolizers with an enzyme deficiency .
p - glycoprotein ( p - gp ) is an adenosine triphosphate - dependent efflux transprotein that is found in the membranes of the enterocytes .
it is expressed by the mdr1 gene in humans and can be found in various organs , including the liver , kidneys , intestinal region , and blood  brain barrier .
p - gp actively pumps its substrates xenobiotics to the extracellular space and decreases their intracellular concentrations .
proton pump inhibitors , including pantoprazole , anti - arrythmic drugs , anticancer drugs , antibiotics , and antidepressant drugs , inhibit p - gp , and therefore the modulation of this pump plays a crucial role in drug  drug interactions [ 12 , 13 ] .
while drugs can cause ar individually , they can also interact with other drugs to bring on the syndrome .
the cyp1 , cyp2 , and cyp3 gene families are overall responsible for drug metabolism , and the similarities between the amino acid sequences within a gene family are at least 40  % , although the level of similarity may increase to 85  % between subgroups . the genetic polymorphisms in these genes
alter the biotransformation of the drug . while fast metabolizers have increased enzyme activity , slow metabolizers show decreased enzyme activity . among these genes ,
theophylline , which is metabolized through this pathway , when used with erythromycin , returns to the cyp1a2 pathway and can not reach toxic concentrations [ 79 ] .
that said , to date , no such theory has been put forward for diclofenac and pantoprazole in the cyp enzyme system .
the fact that they are metabolized through the same subgroup ( 2c ) can be associated with a possible drug interaction .
this possibility of interaction between diclofenac and pantoprazole has been investigated in a randomized crossover trial of 24 subjects , and the results showed that the peak plasma concentrations of diclofenac are sustained in a stable range , and that diclofenac does not affect the pharmacokinetics of pantoprazole , meaning that this combination is completely safe .
however , the results of an in - vitro study using diclofenac as a substrate marker for human liver microsomes suggested the contrary . according to this study , proton pump inhibitors , the strongest one being pantoprazole , carry a strong potential for drug interaction by inhibiting the activity of cyp enzymes , and it was underlined that drug interactions are significantly more pronounced in weak metabolizers with an enzyme deficiency .
p - glycoprotein ( p - gp ) is an adenosine triphosphate - dependent efflux transprotein that is found in the membranes of the enterocytes .
it is expressed by the mdr1 gene in humans and can be found in various organs , including the liver , kidneys , intestinal region , and blood  brain barrier .
p - gp actively pumps its substrates xenobiotics to the extracellular space and decreases their intracellular concentrations .
proton pump inhibitors , including pantoprazole , anti - arrythmic drugs , anticancer drugs , antibiotics , and antidepressant drugs , inhibit p - gp , and therefore the modulation of this pump plays a crucial role in drug  drug interactions [ 12 , 13 ] .
the fda recommends that clinicians check cyp - mediated potential drug interactions routinely . in this case report , a case of diclofenac- and pantoprazole - induced ar is evaluated for drug - interaction mechanisms , and different perspectives are presented . while evaluating the patients with side effects of drugs ,
the cyp and p - gp mechanisms that play roles in drug absorption and distribution should be considered .
written informed consent of the participant was obtained after the nature of the procedures had been fully explained .
the case report was carried out in agreement with the latest version of the declaration of helsinki .
 backgrounddrugs represent one of the etiologic causes of acute rhabdomyolysis ( ar ) with drug - induced rhabdomyolysis most commonly associated with hmg - coa reductase inhibitors . 
 ar etiology can also result from the use of diclofenac , a non - steroidal anti - inflammatory drug , and omeprazole , a proton pump inhibitor . 
 cases of ar triggered by pantoprazole have never before been reported , although it has been observed that its inclusion in multiple drug therapies can result in muscle events.case presentationa 45-year - old man presenting with complaints of fatigue and extensive body pain was diagnosed with acute rhabdomyolysis . 
 his symptoms started on the fourth day of the concomitant use of diclofenac and pantoprazole . 
 the patient was using diclofenac 50-mg tablets once daily for 1  month and pantoprazole 40-mg tablets once daily during the previous week for headaches and pyrosis , resulting in an increase in his creatinine kinase levels to 3114  iu / l ( reference range 
 24190  iu / l ) on the fifth day of concomitant use . 
 his creatinine kinase levels returned to normal and his complaints disappeared after the seventh day of discontinuation of both treatments.discussiona third case of diclofenac - induced rhabdomyolysis was defined in which , different from previous cases , ar was detected during the concomitant use of diclofenac and pantoprazole . 
 the timing of the symptom development and the limited number of ar cases induced by diclofenac and pantoprazole suggested a drug interaction.conclusionthe close relationship between diclofenac and pantoprazole , and the cytochrome p450 and p - glycoprotein systems offers a strong indication that a drug interaction may be occurring . 
 while evaluating the side effects of drugs in patients undergoing monotherapy , clinicians should also consider the mechanisms that play a part in drug absorption and distribution . 