Nearly 1/3 of drug side effects result from drug-drug interactions. Inadequate knowledge of drug-drug interactions may lead to over- or under-treatment. In this article, we will review and introduce the incidence of drug-drug interactions in oncology treatment, their occurrence links and typical examples that are common and easily ignored in clinical practice. Oncology patients are more likely to have drug-drug interactions than other patients. One reason is that antineoplastic drugs often have complex pharmacological profiles, narrow therapeutic windows and steep dose-toxicity curves, and pharmacokinetics and pharmacodynamics may differ significantly between the same patient at different times and between patients. The second reason is that oncology patients often need to receive drugs to treat comorbidities, manage side effects and relieve pain, venous thrombosis, epilepsy and other symptoms simultaneously in addition to antitumor therapy. Another important reason is that the pharmacokinetics of oncology patients may differ compared to other patients, such as decreased drug absorption due to mucositis or malnutrition, altered drug distribution due to edema or changes in plasma binding protein levels, or decreased drug excretion clearance due to hepatic or renal impairment. Drug interactions in oncology treatment are receiving increasing attention. There are few reports on the incidence of drug interactions in oncology patients. In a Norwegian study [1], 4% of oncology-related deaths in hospitalized patients were associated with serious drug interactions. A Canadian study [2] included 100 inpatients with oncology not receiving antineoplastic therapy and found a total of 180 possible drug-drug interactions in 63 patients, 75% of which were moderate to severe. Another Canadian study [3] included ambulatory patients on systemic antineoplastic therapy and applied the drug interaction facts software, version 4.0, and found potential drug interactions in at least 109 of 405 patients (27%). A total of 276 drug interactions were observed, of which 9% were severe and 77% moderate; 49% were supported by one or two pieces of scientific evidence; 55% occurred at the pharmacokinetic level, 25% at the pharmacodynamic level, and 20% were unknown; 87% occurred between non-antineoplastic drugs. 13% (36 cases) included antineoplastic drug interactions, and the most common non-antineoplastic drugs included were, in order of prevalence, Warfarin [15 cases]. Farin [15 cases, interaction with fluorouracil analogs, carboplatin, paclitaxel, etoposide (VP16), and Kenzyme resulted in prolonged INR], hydrochlorperazine [6 cases, interaction with cyclophosphamide (CTX) and 5-fluorouracil (5-FU) resulted in prolonged neutropenia], quinolones (5 cases, interaction with CTX, chemotherapy-associated mucositis may have altered the uptake of quinolones ) and ondansetron (4 cases, interaction with cisplatin, leading to a decrease in cisplatin blood levels). Multifactorial analysis showed an increased number and type of drugs applied and an increased risk of drug interactions in the presence of brain metastases. Drug interactions in oncology therapy can occur at various levels and can be broadly classified as pharmacological, pharmacokinetic and pharmacodynamic [4]. First, pharmacological interactions are those in which drugs interact with each other chemically or physically, leading to changes in characteristics such as efficacy or side effects of one or both drugs after mixing prior to infusion. The addition of mesna to cisplatin leads to inactivation of cisplatin due to the formation of mesna-platinum covalent compounds [5]. When mitomycin is applied in 5% GS (pH 4-5) solution configuration, it is rapidly degraded to inactive mitosen [6]. In contrast, in low pH solutions, paclitaxel and 5-FU form precipitates. When interleukin-2 (IL-2) is infused at a very slow rate, complete loss of drug activity can result due to adsorption by the infusion device, and the recommended dilution of IL-2 is now 5% glucose with 0.1% albumin for prophylaxis [7]. Drug excipients or packaging materials, solvents may also have an effect on pharmacokinetics and/or pharmacodynamics. Adriamycin liposomes are significantly less cardiotoxic than adriamycin, with an approximately 300-fold increase in the area under the plasma concentration-time curve (AUC) and a 250-fold decrease in clearance compared to the free drug, while the volume of distribution is increased by 60-fold [8]. The dose-limiting toxicity also changed from myelosuppression and cardiotoxicity of common adriamycin to hand-foot syndrome. In contrast, the binding of cisplatin to liposomes prevents the drug from effectively reaching its therapeutic target and makes it difficult to form cytotoxic platinum-DNA conjugates, suggesting that cisplatin liposomes are not suitable for clinical applications. When paclitaxel was dissolved in a mixture of polyoxyethylene castor oil and ethanol, the solvents significantly affected the pharmacokinetic characteristics of the drug, resulting in an increase in AUC and a decrease in clearance rate and volume of distribution, and the pharmacokinetics of paclitaxel in clinical studies were characterized by a non-linear state. The possible reason is that the paclitaxel-containing polyoxyethylene castor oil forms colloidal particles in the blood, which prevents the drug from distributing to the tissues. Second, pharmacokinetic interactions occur when one drug affects the absorption, distribution, metabolism, or clearance of another. Pharmacokinetics is where drug interactions have the highest chance of occurring. Absorption: Drug transport proteins and CYP isozymes (CYP3A4 and CYP3A5) in the intestinal epithelium are the major barriers to effective absorption of orally administered drugs. Many chemotherapeutic drugs are substrates of ATP-bound cassette membrane transport proteins, which include P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein (MRP). Transporter proteins are associated with oral bioavailability of antineoplastic drugs as well as drug excretion in the hepatobiliary tract, rectum, and urine. Drugs that affect the activity of these transporter proteins may then affect the absorption of the relevant oral antitumor drugs. Increased expression of transporter proteins is one of the main causes of drug resistance. Distribution: Anticancer drugs can bind to a variety of blood components such as albumin, α1-acid glycoprotein, lipoproteins, immunoglobulins, and red blood cells. The unbound drug is considered to be the biologically active fraction that can leave the circulatory system to reach the therapeutic tissue target. Cytotoxic drugs with high protein binding capacity, such as paclitaxel and Vp-16, may have potential interactions with other protein-binding drugs such as warfarin at the level of drug distribution. Metabolism: Interactions involving the metabolic aspects of chemotherapeutic drugs involve both CYP450 enzymes and non-CYP450 enzymes, the latter being mainly uridine diphosphate glucuronosyltransferase. Drug-drug interactions may exist between anticancer drugs and with non-cytotoxic drugs as long as they are associated with the same metabolic enzymes. The hepatic CYP system is the primary site of antitumor drug metabolism and a common site for drug interactions to occur. Antidepressants, anticonvulsants, cortisol, antituberculosis drugs, and antifungal drugs that are often used clinically to treat tumor comorbidities and complications may often interfere with hepatic CYP450 enzymes and affect the metabolism of the corresponding antineoplastic drugs. Selective 5-hydroxytryptamine reuptake inhibitors, tricyclic antidepressants are partly strong inhibitors of CYP2D6 and may interact with tamoxifen, adriamycin or vincristine, which are metabolized by CYP2D6, when combined with them. Breast cancer patients taking tamoxifen are concurrently administered orally with selective 5-hydroxytryptamine reuptake inhibitors such as paroxetine and fluoxetine, which may affect the conversion of tamoxifen to the more active 4-hydroxytamoxifen and 4-hydroxy-n-desmethyltamoxifen via CYP2D6, thus possibly reducing the patient’s antitumor efficacy [9]. Kivistö KT et al [10] in a phase I clinical study gave patients rifampicin 600 mg/day for 5 days and tamoxifen 80 mg or toremifene 120 mg on day 6, the AUC of tamoxifen and toremifene decreased by 86% and 87%, respectively, compared to the control group, and both plasma peak concentrations decreased by The AUC of tamoxifen and toremifene decreased by 86% and 87%, respectively, compared with the control group, and the peak plasma concentration decreased by 55%, so the anti-estrogenic effect of the drug may be reduced when combined with rifampin. In another phase I clinical study [11], 14 healthy subjects received imatinib 400 mg on days 1 and 15 and rifampicin 600 mg/day on days 8-18, and the AUC and peak plasma concentration of imatinib decreased by 74% and 54%, respectively, and clearance increased by 385% when rifampicin was combined, so the combination of rifampicin may not lead to therapeutic levels of imatinib. When combined with gefitinib, rifampicin reduces the former AUC by 85%, and it is recommended to increase the dose of gefitinib to 500 mg/day. In contrast, cyclophosphamide and isocyclophosphamide need to be metabolized by hepatic CYP450 enzymes to active products with antitumor effects, and in studies of hepatocellular carcinoma cell lines [12], concomitant application of rifampin facilitates enhanced metabolic activation of these two drugs. Anticonvulsant drugs and cortisol induce most CYP isozymes and enhance the metabolism of antitumor drugs. For example, phenytoin is a strong inducer of CYP3A4 and can alter the pharmacokinetics of antitumor drugs metabolized with the participation of this enzyme. Studies suggest that the combination of phenytoin with gefitinib, irinotecan, paclitaxel and other drugs can lead to a decrease in the blood concentration of antitumor drugs, thus requiring an increase in drug dose. The antifungal drugs itraconazole and ketoconazole are inhibitors of CYP3A4, and their effects can be enhanced by increasing blood concentrations when combined with drugs such as imatinib and gefitinib. Drug metabolism level interactions can also occur in the non-CYP enzyme segment. In Japan, 15 cancer patients with herpes simplex died from the combination of oral mangiferine and the antiviral nelivudine. The patients had significant 5-FU overdose symptoms such as diarrhea, mucositis, leukopenia, and thrombocytopenia. Pharmacological studies in rats found [13] high 5-FU concentrations in plasma, bone marrow, liver, and small intestine, and all animals died within 10 days; rats receiving murfuralidine or nelivudine alone survived 20 days without significant signs of toxicity. Further studies revealed that the intestinal conversion of nelivudine to (E)-5(- 2-bromovinyl) uracil irreversibly inhibits the action of dihydropyrimidine dehydrogenase, a key enzyme in the metabolism of fluorouracil analogs. Pharmacokinetic level interactions can also occur during sequential administration. In animal studies [14] cisplatin applied before paclitaxel had a synergistic antitumor effect, but also significantly increased complications and mortality, and paclitaxel applied before cisplatin had an increased therapeutic index, with the highest index applied 48 hours apart. In a phase I clinical trial [15], cisplatin was applied before paclitaxel, and more pronounced myelosuppression occurred because cisplatin affected CYP enzymes involved in paclitaxel metabolism, resulting in a 25% reduction in paclitaxel clearance.Holmes FA et al [16] studied the effect of sequential sequence of adriamycin and paclitaxel administration on drug metabolism in patients with advanced breast cancer and found that the peak blood concentration of adriamycin was increased when paclitaxel was administered first The authors recommended that adriamycin be administered first when the two drugs are given sequentially. In addition, antineoplastic drugs may also cause changes in the metabolism and absorption of drugs used to treat other diseases and require clinical attention, notably oral coumarins and antiepileptic drugs. The mechanism of the effect of capecitabine on warfarin is not clear, but may be related to the downregulation of CYP2C9 enzyme function by capecitabine.Kolesar JM et al [18] reported that 5 patients treated with 5-FU chemotherapy while taking warfarin had an increased risk of bleeding and required a mean 44% reduction in warfarin dose. Carboplatin, VP-16, isocyclophosphamide, paclitaxel, Kinzel, gefitinib, and Herceptin have also been reported in the literature to prolong patients’ INR and increase the risk of bleeding when used with warfarin. Therefore, coumarin anticoagulants should be combined with these drugs with close monitoring of the patient’s INR and timely adjustment of the dose of warfarin. Brickell K et al [19] reported two patients who combined capecitabine with phenytoin and developed central nervous system symptoms of phenytoin toxicity after 6-8 weeks, and the mechanism was thought to be related to the downregulation of CYP2C9 enzyme function by capecitabine. Another patient on combined fluorouracil and phenytoin also developed symptoms of phenytoin toxicity such as hyperreflexia, nystagmus and muscle tremor, thus requiring phenytoin dose adjustment.Neef C et al [20] reported a case of grand mal seizure in a young woman taking antiepileptic drugs with concurrent cisplatin and adriamycin chemotherapy. Drug concentration monitoring revealed that plasma concentrations of carbamazepine and valproate decreased two days after the start of chemotherapy, recovered two to three days after cisplatin was stopped, and phenytoin concentrations decreased to 37% despite being administered intravenously. Cases of decreased phenytoin blood concentrations have also been reported in patients treated with cisplatin in combination with carbamustine or vincristine and bleomycin or azelnimethamine and tamoxifen. Therefore, phenytoin concentrations need to be increased during the above chemotherapy to control epilepsy. Clearance Most antineoplastic drugs are cleared metabolically, whereas methotrexate and platinum compounds are mainly secreted by glomerular filtration and renal tubules. Certain penicillins, such as amoxicillin, meloxicillin, piperacillin and benzocillin, have been reported in the literature to inhibit renal tubular secretion of methotrexate and reduce clearance of the latter.Titier K [21] et al. reported that in an 18-year-old patient with osteosarcoma treated with a second cycle of single-agent methotrexate 15 g chemotherapy and concomitant benzocillin 1 g Q8h, the patient’s peak methotrexate blood concentration was significantly increased and Blum R et al [22] reported two cases of osteosarcoma patients treated with high-dose methotrexate chemotherapy who experienced significantly slower clearance of methotrexate due to vancomycin application within the first ten days of chemotherapy, and renal hemograms suggesting impaired renal function. Third, pharmacodynamic interactions often occur because two classes of drugs have similar mechanisms of action, or one drug causes electrolyte alterations that affect the other, and thus can interact pharmacodynamically in a synergistic, additive, or antagonistic manner. In terms of antitumor effects, the combination of 5-FU with calcium folinate has shown higher therapeutic response rates than 5-FU alone in patients with colon cancer. Synergistic antitumor effects of cisplatin and gemcitabine were observed in non-small cell lung cancer cell lines [23], while in four mesenchymal thyroid cancer cell lines [24], Kenzyme was synergistic with both applied before cisplatin, while cisplatin was antagonistic with Kenzyme. In terms of toxicity, cisplatin and doxorubicin combination showed neurotoxicity in 75% of 55 patients when the cumulative dose exceeded 200 mg/m2, with an increased incidence and extent compared to alone [25].Tomirotti M et al [26] reported that patients without cardiac symptoms after adriamycin treatment could induce recurrent reversible precordial pain, chest tightness and ECG ischemia after cisplatin application manifestations. In a phase I study [27], five patients developed severe hearing loss after receiving carboplatin 200-300 mg/m2, and all patients had a recent history of aminoglycoside antibiotic use,considering an interaction between the two drugs. Isocyclophosphamide in combination with cisplatin can aggravate cisplatin-induced hearing impairment [28]. the combination of G-CSF or GM-CSF with vincristine can lead to severe peripheral neuropathy [29]. In addition, the dangers of over-the-counter medications such as vitamins, non-steroidal anti-inflammatory drugs (NSAIDs), herbs, and foods when combined with chemotherapy should not be overlooked, and lack of awareness often leads to the possibility of sudden, unpredictable, and serious toxicities for the physician and patient. Acidification of urine by high doses of vitamin C, when combined with high doses of MTX, may lead to acute renal insufficiency due to the non-water soluble metabolite of MTX, 7-hydroxy MTX, which precipitates in the renal tubules under low pH conditions [30]. When MTX and pemetrexed are applied in combination with NSAID side effects are significantly increased, which may be related to competitive secretory excretion in the renal tubules, etc. Therefore, it is recommended not to combine NSAID within ten days of high-dose MTX application and to discontinue NSAID before and after the application of pemetrexed in patients with mild to moderate renal insufficiency. In conclusion, the mechanisms of drug interactions in oncology therapy have not been fully elucidated, and the number of drug applications The increase in the number of drug applications and new combinations have made drug-drug interactions more complex. In order to obtain the maximum therapeutic effect, more theoretical and clinical information about drug-drug interactions needs to be collected, and the synergistic effects between drugs should be used rationally to avoid antagonistic effects. Regular clinical checks with patients on medication use are needed, with particular attention to the application of drugs other than antineoplastic therapy. Special attention to drug-drug interactions is needed for patients taking drugs such as warfarin, rifampin, antiepileptic drugs, antidepressants, and antihypertensive drugs.