Pharmacokinetic Drug-Drug Interactions:

A Systematic Review of the Cytochrome P450 (CYP) Isoenzyme 3A4

Ahmad Ainurofiq¹*, Lutvi Ismaya²

¹Department of Pharmacy, Sebelas Maret University, Ir. Sutami 36A, Surakarta 57126, Indonesia.

²Pharmacy Program, School of Vocational, Sebelas Maret University,

Kolonel Sutarto 150K, Surakarta 57126, Indonesia.

*Corresponding Author E-mail: rofiq@mipa.uns.ac.id

ABSTRACT:

The cytochrome P450 (CYP) isoenzyme 3A4 or CYP3A4 is a major drug-metabolizing enzyme that has the potential to cause pharmacokinetic drug-drug interactions. Primary research studies have demonstrated CYP3A4-mediated drug-drug interactions through a variety of mechanisms. However, there has been no review during the last 10 years of pharmacokinetic drug-drug interactions mediated by CYP3A4 isoenzymes. It is necessary to systematically review the pharmacokinetic drug-drug interactions mediated by CYP3A4. Source review of articles were retrieved from the PubMed and Scopus databases. The preparation of keywords through the population, intervention, comparison, and outcomes (PICO) method written based on the Boolean operator. Reporting the results of the paper search is presented in the Prisma version 1 2020 flowchart. The risk of bias assessment used COHORT tools and Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tools. Data was analyzed narratively. Pharmacokinetic drug interactions are mediated by CYP3A4 through the mechanism of induction, activation, inhibition, and inactivation. Induction or activation of CYP3A4 can cause an increase in CYP3A4 expression, so that the drug is metabolized more quickly and has the potential to lose drug efficacy. Inhibition and inactivation of CYP3A4 causes plasma drug levels to increase and drug elimination time to last longer. CYP3A4 plays a major role in the bioactivation of drugs that cause hepatotoxicity through the formation of reactive metabolites. The use of drugs needs to be monitored to avoid pharmacokinetic drug interactions.

KEYWORDS: Drug-drug interaction, CYP3A4, Mechanism, Pharmacokinetic, Drug metabolism.

INTRODUCTION: 

Drug interactions are the effects or actions of drugs that change or are modified due to interactions with one or more other drugs^1-3. Adverse drug reactions are drug effects that are mild to toxic, including hypersensitivity and anaphylaxis. Drug incompatibility is a chemical or physical action that occurs between two or more in vitro conditions⁴. There are three categories of drug interaction mechanisms⁵, which include pharmaceutical interactions (in vitro)^6,7, pharmacokinetics^8-10, and pharmacodynamics^11,12. Pharmacokinetic drug interactions involve processes of absorption, distribution, metabolism, and excretion, all of which are associated with treatment failure or toxicity¹³.

Pharmacokinetic drug-drug interactions occur when a drug changes the disposition (absorption, distribution, metabolism, elimination) of the co-administered drug. Pharmacokinetic interactions lead to an increase or decrease in the plasma concentration of the drug. The intensity of these modifications varies, but may cause association contraindications¹⁴. Drug interactions in the distribution process consist of three mechanisms, namely metabolism inhibition, metabolism induction, and changes in hepatic blood flow¹⁵. Inhibition of drug metabolism applies to drugs or substances that are substrates for cytochrome P450 (CYP) enzymes¹⁶.

CYP is an enzyme that can cause drug toxicity due to enzyme induction factors, enzyme inhibition (both reversible and irreversible), and pharmacogenetics. Pharmacogenetic approaches that take into account CYP genotype and/or phenotype by individualizing treatment regimen¹⁷. Inhibition or induction of the CYP system, especially CYP3A4, play an important role in the pharmacokinetic interaction of drugs by changing the concentration of drugs or toxic metabolites in the target tissue of action¹⁸. CYP enzymes belong to a superfamily of monooxygenases whose structures are interrelated and hydrolyze many physiological molecules (such as steroids and fatty acids) and xenobiotic compounds (such as drugs, carcinogens, and environmental substances). In humans, there are approximately 100 CYP isoenzymes with differing but overlapping specificities. These isoenzymes generally have two main components, namely an electron donor reductase system that uses an electron transfer from NADPH and a substrate-bound CYP¹⁹. Its catalytic activity plays an important role in various fields such as drug-drug interactions and endocrine function²⁰.

CYP is a major source of variability in pharmacokinetics and drug responses. These enzymes are responsible for the biotransformation of most foreign substances, accounting for the metabolism of 70-80% of all drugs in clinical use. The highest expression forms in the liver were CYPs 3A4, 2C9, 2C8, 2E1, and 1A2, while 2A6, 2D6, 2B6, 2C19, and 3A5 were less abundant, and CYPs 2J2, 1A1, and 1B1 were expressed in extrahepatic tissues. The expression of each CYP is influenced by a unique combination of mechanisms and factors including genetic polymorphisms, xenobiotic induction, cytokine regulation, hormones, disease, gender, age, and others²¹. In addition, polypharmacy (prescribing more than five types of drugs) has the potential to cause drug-drug interactions²².

Based on the background description above, it is known that there is a potential for drug interactions based on pharmacokinetic properties mediated by CYP3A4 isoenzymes. However, there are no studies that conclude the pharmacokinetic mechanism of drug interactions mediated by CYP3A4 isoenzymes. Therefore, it is necessary to review the pharmacokinetic drug interactions mediated by the CYP3A4 isoenzyme based on research data from the results of a literature review that often occurs with systematic assessment. The urgency this study is expected to provide a systematic description of the pharmacokinetic drug interactions mediated by the CYP3A4 isoenzyme. The benefit of this research for the development of science, especially in the field of pharmaceutical technology and clinical pharmacy. For the community, this research is expected to be the basis for the decision to consume a certain drug because it can cause pharmacokinetic interactions mediated by the CYP3A4 isoenzyme.

MATERIALS AND METHODS:

This systematic review summarizes the results of primary research related to pharmacokinetic drug-drug interactions mediated by CYP3A4 for the period 2010–2020. The systematic review of the literature was conducted December 2020–December 2021. The collection of papers sourced from Scopus and PubMed were carried out fromJanuary to October 2021. This study aims to summarize the primary research on the pharmacokinetic mechanism of drug interactions mediated by the CYP3A4 isoenzyme. The initial search approach was to compile keywords through the population, intervention, comparison, and outcome (PICO) method, because keywords obtained in this manner are used to obtain papers that are in accordance with the theme and as a reference in research discussions. The arrangement of keywords is written based on the Boolean operator with the conjunction "AND" to get a wider range of results. The search used the obtained keywords as follows: (drug-drug interaction) AND (P450 (CYP) 3A4) AND (mechanism). The inclusion criteria were as follows: each paper was written in English, was published 2010–2020, and followed a primary research study design examining in vitro and in vivo pharmacokinetic drug interactions mediated by CYP3A4^23-25.

The risk of bias assessment for the preclinical in vitro studies used the Consolidated Standards of Reporting Trials (CONSORT) protocol. Paper quality was assessed using CONSORT, which consists of 15 items to assess individual parts of a paper (abstract, introduction, methods, results, discussion, and other information). The CONSORT checklist was originally developed to assess the quality of dental studies in vitro and has been used in the assessment of mechanistic studies on SARS-CoV-infected cells in vitro with modifications according to the study^26,27.

The risk of bias assessment for the in vivo studies used the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) method. The SYRCLE checklist consists of 10 questions to assess different types of bias (selection bias, detection bias, performance bias, attrition bias, reporting bias, and others). The possible answers for each item are yes, no, and unclear, which indicate low, high, and unclear risk of bias. The SYRCLE tool was developed for animal studies and adapted from Cochrane's Risk of Bias Tool. The assessed bias risks are selection, performance, detection, attrition, and reporting bias. Selection bias results from inadequate randomization and allocation concealment. Performance bias depends on placement of animals in random cages and concealment from caregivers and operators. Detection bias occurs when selection of animals is inadequate for outcome assessment and concealment from examiners. Friction bias is related to animal omissions and incomplete or uneven exclusions. Reporting bias occurs due to the selection of reported results²⁸.

Figure 1: PRISMA flow chart for papers selection and evaluation

RESULT:

The search resulted in 396 (339 from Scopus and 57 from PubMed) studies. The initially identified papers duplicated by one search engine or by both search engines, so 13 studies were removed. Papers (163) whose title and abstract did not match the research topic were excluded. Eighteen papers that could not be accessed and two papers with results that did not match the research topic were excluded. Thus, 41 papers met the inclusion criteria for further analysis. The results of the search are presented in the Prisma flow chart in Figure 1

DISCUSSION:

The primary consequence of pharmacokinetic drug-drug interactions is increasing or decreasing drug levels in plasma and tissues. The inhibition of drug-metabolizing enzymes  results in elevated plasma drug levels. The effect of the resulting increase in pharmacological activity depends on the therapeutic window. Inhibiting enzyme activation and prodrug induction reduces the effectiveness of treatment. Inhibiting the primary pathway of drug metabolism diverts metabolism to the secondary pathway, which is problematic if toxic products are created²⁹.

Drug metabolism involves the catalysis of a class of mixed-function enzymes (CYP). One of the most abundant drug-metabolizing enzymes in this class is CYP3A4. The CYP3A4 isoenzyme is a member of the CYP3A enzyme family, consisting of four genes (CYP3A4, CYP3A5, CYP3A7, and CYP3A43) arranged on the CYP3A locus. An increase in CYP3A4 expression indicates an increase in the production and metabolic activity of the enzyme, so that the drug level in the plasma decreases. Likewise, a decrease in CYP3A4 expression indicates lower enzyme levels and decreased metabolic activity, resulting in higher plasma drug level³⁰.

The purpose of this systematic review was to determine which drugs cause pharmacokinetic drug-drug interactions mediated by the CYP3A4 isoenzyme and to determine the pharmacokinetic mechanism of drug interactions mediated by the CYP3A4 isoenzyme based on the results of a search for journal articles published 2010–2020. The focus was on drug interactions mediated by CYP3A4 because it is the most highly expressed form in the liver³¹. CYP3A4 is a Phase I enzyme found in large quantities in the liver and intestines which metabolizes approximately 50% of therapeutic drugs³². The pharmacokinetic drug-drug interactions mediated by CYP3A4 revealed by the research results are the mechanisms of induction, activation, inhibition, and inactivation.

Induction and Activation:

Drug interactions through CYP3A4 induction can lead to decreased bioavailability (Table 1) and toxic effects (Table 2). Table 1 lists CYP3A4 inducers and activators that cause a decrease in bioavailability.

Table 1. CYP3A4 inducers and activators that cause a decrease in drug bioavailability

Drug Name(s)	Test Media	Description	Author (Year)
Carbamaze-pine	HepG2 cells, primary cultured human hepatocytes	Inducer CYP3A4 via HDAC1	Wu et al . (2012)^33
Mitotane	Human hepatocytes	Inducer of CYP3A4 via SXR activation	Takeshita et al. (2013)^34
Metolazone	Human hepatocytes, human intestinal cells	Inducer of CYP3A4 via hPXR activation	Banerjee and Chen, (2014)^35
Aflutinib	Human liver microsomes	Strong inducer of CYP3A4	Liu et al. (2020)^36
Derivatives of acridinone (C-1305 and C-1311)	HCT116 cells (colon cancer cells)	Very strong activator of CYP3A4 and UGT1A10	Pawlowska et al. (2020)^37

HDAC1, histone deacetylase 1; CYP, cytochrome P450, SXR, steroid and xenobiotic receptor; hPXR, human pregnane X receptor; UGT1A10, UDP-glucuronosyltransferase family 1 member A10)

As seen in Table 1, carbamazepine³³, mitotane³⁴, metolazone³⁵, aflutinib³⁶, and the acridinone derivatives C-1305 and C-1311³⁷ induce the expression of CYP3A4 or activate CYP3A4 activity. CYP3A4 occurs through several mechanisms. For example, its induction by carbamazepine is mediated by histone deacetylase 1 (HDAC1)³³ and its induction by mitotane³⁴ and metolazone³⁵ is mediated by the steroid and xenobiotic receptor (SXR), commonly called the human pregnane X receptor (hPXR). An inducer of a metabolizing enzyme (i.e., CYP) increases the synthesis of that enzyme. The combination of an inducing drug with drugs that are CYP3A4 substrates can increase the rate of substrate drug metabolism, so that drug levels and efficacy decrease³².

The systematic review revealed drug-drug interactions that cause hepatotoxicity due substrate drugs being combined with CYP3A4 inducers. As seen in Table 2, certain combinations of drugs with CYP3A4 inducers cause toxic effects.

Table 2. Combinations of drugs with CYP3A4 inducers that cause toxic effects

Drug name	Test media	Mechanism of interaction	Author (Year)
Clozapine	Human liver microsomes	CYP3A4 as the major enzyme in the bioactivation of clozapine that causes hepatotoxicity	Dragovic et al. (2013)^38
Saquinavir and rifampicin (CYP3A4 inducers)	Mice, human liver microsomes	Formation of two metabolites (α-hydroxyaldehyde and a primary amine); a three-fold increase in the toxicity of saquinavir	Li et al. (2014)^39

The inhibition or induction of enzymes in the CYP system, particularly CYP3A4, plays an important role in drug interaction pharmacokinetics by altering the concentration of the drug or toxic metabolite in the target tissue¹⁸. CYP induction can also lead to the formation of toxic reactive metabolites³². As seen in Table 2, the combination of clozapine and CYP3A4 inducers forms reactive metabolites³⁸. Thus, CYP3A4 is the main enzyme involved in clozapine bioactivation, with an eight-fold increase in the reactive metabolite that causes hepatotoxicity. In addition, drug-drug interactions occur between saquinavir and the CYP3A4 inducer rifampicin. The combination of saquinavir with a CYP3A4 inducer increases the formation of the reactive metabolite α-hydroxyaldehyde(M229), which can increase the toxicity of saquinavir³⁹. From these studies, it is known that toxic effects can occur due to the formation of reactive metabolites from drugs combined with CYP3A4 inducers.

Inhibition:

Pharmacokinetic drug interactions mediated by CYP3A4 may also occur through inhibition. Inhibition of CYP3A4 activity is divided into two main mechanisms, namely reversible inhibition and mechanism-based inactivation (including quasi-irreversible and irreversible inhibition). Reversible inhibition is classified as competitive, noncompetitive, and mixed³². Table 3 shows the mechanism of pharmacokinetic drug-drug interaction through reversible inhibition of CYP3A4.

Table 3. Inhibition of CYP3A4 through a reversible mechanism

Drug Name(s)	Test Media	Description	Author (Year)
Competitive reversible inhibition of CYP3A4 and other enzymes
Clarithromycin	Human hepatocyte suspension	Weak inhibitor of CYP3A4 and CYP3A5	Michaud and Turgeon (2010)^40
Artemisinin (antimalarial)	Human liver microsomes	Strong inhibitor of CYP2B6 and weak inhibitor of CYP3A4	Xing et al. (2012)^41
Ethambutol	Human liver microsomes	Strong inhibitor of CYP1A1 and CYP2E1 and a moderate inhibitor of CYP2A6, CYP2C9, and CYP3A4	Lee et al. (2014)^42
MDEA and DDEA	Human liver microsomes	Inhibitor of CYP3A4	McDonald et al. (2015)^43
AM-2201 synthetic cannabinoid (narcotic)	Human liver microsomes	Potent inhibitor of CYP3A4, CYP2C9, UGT1A3, and UGT2B7	Kim et al. (2017)^44
Noncompetitive reversible inhibition of CYP3A4 and other enzymes
Norendoxifen	Incubation microsomes	Noncompetitive inhibitor of CYP3A19, CYP3A19, and CYP2 and competitive inhibitor of CYP2A6 and CYP2C19	Liu et al. (2013)^45
MAM-2201 synthetic cannabinoid (narcotics)	Human liver microsomes	Noncompetitive inhibitor CYP3A4, competitive inhibitor of CYP2C9, potent inhibitor of CYP2C8, and reversible inhibitor of UGT1A3	Kong et al. (2017)^46
Asenapine (atypical antipsychotic)	Microsomes,human liver supersomes	Weak noncompetitive inhibitor of CYP3A4, mixed-mechanism CYP1A2 inhibitor, and competitive CYP2D6 inhibitor	Wojcikowski et al. (2020)^47
Reversible inhibition of CYP3A4 via a mixed mechanism
Levomepromazine (phenothiazine neuroleptic)	Human liver microsomes	Competitive inhibitor of CYP3A4 and CYP2D6; mixed-mechanism inhibitor of CYP13A4	Basińska-Ziobroń et al. (2015)^48

MDEA, mono-N-desethylamiodarone; DDEA, N-didesethylamiodarone; AM-2201, [1-(5-Fluoropentyl)-1H-indol-3-yl](1-naphthyl)methanone; MAM-2201, 4'-methyl-AM-2201

As seen in Table 3, several CYP3A4 inhibitors use a reversible mechanism. Competitive inhibitors compete for the active site of the enzyme with the substrate³². Drugs that are competitive inhibitors of CYP3A4 include clarithromycin⁴⁰, artemisinin⁴¹, ethambutol⁴², mono-N-desethylamiodarone (MDEA), N-didesethylamiodarone (DDEA)⁴³, and [1-(5-Fluoropentyl)-1H-indol-3-yl](1-naphthyl)methanone (AM-2201)⁴⁴. Noncompetitive inhibition occurs when the drug binds to the enzyme at a site other than the active site and does not compete for the active site³².Noncompetitive CYP3A4 inhibitors include norendoxifen⁴⁵, the synthetic cannabinoid 4'-methyl-AM-2201 (MAM-2201)⁴⁶, and asenapine⁴⁷. In the case of mixed inhibition, the inhibitor and substrate can bind to the active site of the enzyme simultaneously³².CYP3A4 inhibition by a mixed mechanism occurs with levomepromazine. In the case of mixed inhibition, the K_m (values of Michaelis-Menten constants) and V_max (the maximum velocities of the reactions) values changed at different inhibitors concentrations. In the case of competitive inhibition, the V_max value did not significantly change, while the K_m was altered at different inhibitor concentrations. The interaction between levomepromazine and CYP3A4 substrates, such as benzodiazepines, CCB antagonists, macrolides, and testosterone, needs carefully monitored⁴⁸.

Mechanism-based CYP3A4 inhibition depends on time, concentration, and nicotinamide dinucleotide phosphate (NADPH). Time-dependent inhibition of CYP refers to a change in potency during an in vitro incubation or in vivo. Concentration-dependent inhibition is drug concentration in the in vitro or in vivo after a sufficient of incubation time. Table 4 describes the mechanism of pharmacokinetic drug-drug interactions through mechanism-based CYP3A4 inhibition.

Table 4. Mechanism-based CYP3A4 inhibition

Drug Name(s)		Test Media		Description	Author (Year)
Time-dependent inhibitors of CYP3A4
Oncology drugs (docetaxel, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, sirolimus, sorafenib, sunitinib, and temsirolimus)	Human liver microsomes		Inhibitors of CYP3A (CYP3A4 and CYP3A5)			Kenny et al. (2012)^49
Sertraline (selective serotonin reuptake inhibitor)	Human liver microsomes		Time-dependent inhibitor of CYP3A4			Masubuchi and Kawaguchi (2013)^50
Propiverine (antimuscarinic)	Human liver microsomes		Time-dependent inhibitor of CYP3A4 and CYP2D6			Dahlinger et al. (2017)^51
Panobinostat	Human liver microsomes		Competitive inhibitor of CYP2D6, time-dependent inhibitor of CYP3A4/5, and weak inhibitor of CYP2C19			Einolf et al. (2017)^52
Concentration-dependent inhibitors of CYP3A4
Nateglinide		Human liver microsomes		Very weak inhibitor of CYP1A1/2, CYP2C9, CYP2D6, CYP2E1, and CYP3A4	Takanobashi et al. (2010)^53
Tanespimycin and 17-amino-17-demethoxygeldanamycin		Human liver microsomes		Moderate inhibitor of CYP3A4/5 and CYP2C19	Gan et al. (2011)^54
β-lapachone (candidate anticancer)		Human liver microsomes		Inhibitors of CYP1A2, CYP2A6, CYP2C9, CYPC19, CYP2D6, and CYP3A4	Kim et al. (2013)^55
Reversible inhibition CYP3A4 via a mixed mechanism
Levomepromazine  (Phenothiazine neuroleptic)		Human liver microsomes		Competitive inhibitor of CYP2D6, mixed-mechanism inhibitor of CYP1A2 and CYP3A4	Basińska-Ziobroń et al. (2015)^48

Table 5: Drugs as CYP3A4 inhibitors

Drug Name(s)	Test Media	Description	Author (Year)
INH, PAS, and macrolides	Human hepatocytes (HepaRG cells)	Weak inhibitors of CYP3A4	Horita and Doi (2014)^56
5α-androstane-3α, 17β-diol androgen derivatives	Recombinant cell-enzymatic dibenzylfluoroscein	Weak inhibitor of CYP3A4 and CYP2D6	Ayan et al. (2014)^57
Gevokizumab	Human hepatocytes	Attenuates, but does not abolish, IL-1β-mediated functional repression of CYP3A4	Moreau et al. (2017)^58

INH, isoniazid/isonicotinic acid hydrazide; PAS, para-aminosalicylic acid;

*Study did not explain the mechanism of inhibition of CYP3A4

As seen in Table 4, time-dependent CYP3A4 inhibitors include oncological drugs (such as docetaxel, dasatinib, erlotinib, everolimus, imatinib, lapatinib, nilotinib, pazopanib, sirolimus, sorafenib, sunitinib, and temsirolimus)⁴⁹, sertraline⁵⁰, propiverine⁵¹, and panobinostat⁵². Concentration-dependent inhibitors of CYP3A4 include nateglinide⁵³,tanespimycin, 17-amino-17-demethoxygeldanamycin⁵⁴, and β-lapachone⁵⁵.

Several drugs have not been studied further regarding the mechanism of CYP3A4 inhibition because they are weak inhibitors of CYP3A4 and the potential for drug-drug interactions is not clinically significant. These drugs include isoniazid (isonicotinic acid hydrazide, INH), para-aminosalicylic acid (PAS), macrolide antibiotics⁵⁶, the androgen derivative 5α-androstane-3α, 17β-diol⁵⁷, and gevokizumab⁵⁸. Seen in Table 5 is a list of drugs that are CYP3A4 inhibitors (Table 5).

Irreversible Inhibition or Irreversible Inactivation:

Irreversible inhibition of CYP3A4 due to inactivation or enzyme complexation occurs when some therapeutic drugs are converted by CYP enzymes into reactive metabolites capable of covalently binding to the CYP3A4 protein or heme moiety³². The drugs listed in Table 6 cause CYP3A4 inactivation.

Irreversible inhibition leads to time-dependent loss of CYP3A4 activity and cannot be recovered over the desired time span³². As seen in Table 6, irreversible inhibitors or CYP3A4 inactivators include mertansine⁵⁹, 2-methylindole (2-MI)⁶⁰, zolpidem⁶¹, amiodarone, dronedarone, N-desethylamiodarone (NDEA), and N-desbutyldronedarone (NDBD) combined with rivaroxaban⁶².

Table 6: Drugs that cause irreversible inhibition or inactivation of CYP3A4

Drug Name(s)	Test Media	Description	Author (Year)
Inactivation of CYP3A4 through an irreversible mechanism
Mertansine (cancer therapy)	Human liver microsomes	Irreversible inhibitor of CYP3A4, competitive inhibitor of CYP2D6, CYP2C8, UGT1A3, UGT1A4, and UGT1A1	Choi et al. (2020)^59
2-MI	Human liver microsomes, Sprague–Dawley rats	Inactivation of CYP3A (CYP3A4 and CYP3A5) due to reactive intermediates irreversibly forming covalent bonds	Wong et al. (2010)^60
Zolpidem	Human liver microsomes	Inactivation of CYP3A (CYP3ACYP3A4 and CYP3A5) irreversibly	Polasek et al. (2010)^61
Amiodarone, dronedarone, NDEA, and NDBD-Rivaroxaban (substrate probe CYP3A4)	Supersomes with human recombinant CYP	Inhibitor reversibly and inactivator based on the mechanism of irreversible CYP3A4	Cheong et al. (2017)^62
Inactivation of CYP3A4-based mechanisms
SCH 66712 (human dopamine D4 receptor antagonist) and EMTPP	Human CYP3A4 recombinant	Inactivation potent of CYP3A dependent of concentration, time, and NADPH	Bolles et al. (2014)^63
Dronedarone (antiarrhythmic agent), NDBD	Human liver microsomes	Mechanism-based inactivation of CYP3A4 and CYP3A5	Hong et al. (2016)^64
C-1311 (antitumor)	Human recombinant cells	Selective mechanism-based CYP1A2 and CYP3A4 inactivators	Potęga et al. (2016^a)^65
C-1305 (antitumor)	Human recombinant cells	Selective mechanism-based CYP1A2 and CYP3A4 inactivators	Potęga et al. (2016^b)^66

2-MI, 2-methylindole; NDEA, N-desethylamiodarone (NDEA), NDBD, N-desbutyldronedarone, SCH 66712, 5-fluoro-2-[4-[(2-phenyl-1H-imidazol-5-yl)methyl]-1-piperazinyl]pyrimidine; EMTPP, 1-[(2-ethyl-4-methyl-1H-imidazol-5-yl)methyl]-4-[4-(trifluoromethyl)-2-pyridinyl]piperazine; NADPH, nicotinamide dinucleotide phosphate

Table 7: Drug interactions with CYP3A4 inhibitor and inactivator

Drug Name(s)	Test Media	Description	Author (Year)
Arteether α/β-ketoconazole                  (CYP3A4 inhibitors)	Liver of healthy Swiss mice	Ketoconazole (a potent inhibitor of CYP3A4) slows Arteether α/β metabolism and prolongs increases in blood plasma drug levels	Tripathi et al. (2013)^67
Pioglitazone-domperidone (CYP3A4 inhibitor)	Human liver microsomes	Pioglitazone inhibits domperidone metabolism depending on concentration and time	Youssef et al. (2014)^68
Sunitinib (tyrosine kinase inhibitor)-Ketoconazole (CYP 3A4 inhibitor)	Mice (liver, kidney, and brain tissue)	Ketoconazole inhibits metabolism sunitinib	Chee et al. (2015)^69
Verapamil-HCPT	Sprague–Dawley rats	Verapamil inhibits the activity of CYP3A4 and P-gp, increases the plasma peak, and decreases the oral clearance	Xing et al. (2020)^70
Bedaquiline-CYP3A4	Plasma from Wistar rats	Ciprofloxacin and fluconazole inhibit the pharmacokinetics of bedaquiline	Kotwal et al. (2019)^71
Triazolam-diltiazem	Mechanistic physiology (gut and liver)	Diltiazem (CYP3A4 inactivator) competitively increases triazolam levels depending on time	Yeo et al. (2010)^72

HCPT, hydroxycamptothecin

Mechanism-based CYP3A4 inactivators include 5-fluoro-2-[4-[(2-phenyl-1H-imidazol-5-yl)methyl]-1-piperazinyl]pyrimidine (SCH 66712), 1-[(2-ethyl-4-methyl-1H-imidazol-5-yl)methyl]-4-[4-(trifluoromethyl)-2-pyridinyl]piperazine (EMTPP)⁶³, dronedarone, and NDBD⁶⁴. Long-term use the of the acridinone derivatives 5-dimethylaminopropylamino-8-hydroxytriazoloacridinone (C-1305) and 5-diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) in colon cancer cells (HCT116) increases CYP3A4 activity³⁷, indicating that C-1305 and C-1311 are strong inducers of CYP3A4. In contrast to the research of Potęga et al., which uses a non-cellular system^65,66, this study revealed that C-1305 and C-1311 are selective mechanism-based inactivators of the ability of CYP3A4 to catalyze 6β-hydroxylation of testosterone (Table 6). It can be concluded that inhibition of the catalytic activity of CYP3A4 is not generated through a direct interaction between the compound and the CYP enzyme. Inhibition of the catalytic activity of CYP3A4 by C-1305 and C-1311 through cellular regulatory pathways is stronger than the direct inhibitory feature of the drug³⁷. Drug interactions with CYP3A4 inhibitors or inactivators in are shown in Table 7.

As seen in Table 7, there are interactions between the following drugs and inhibitors of CYP3A4: Arteether α/β⁶⁷, pioglitazone⁶⁸, sunitinib⁶⁹, hydroxycamptothecin (HCPT)⁷⁰, and bedaquiline⁷¹. The combination of these drugs with CYP3A4 inhibitors causes an increase in peak plasma levels and a decrease in oral clearance⁷⁰, thereby prolonging increases in blood plasma levels of the drug⁶⁷. Interactions between triazolam and the CYP3A4 inactivator diltiazem also occur, competitively inactivating CYP3A4 expression and leading to a time-dependent increase in plasma triazolam levels⁷².

CONCLUSION:

The systematic review of the literature reveals pharmacokinetic drug interactions that have been tested preclinically. Drugs can interact with other drugs through CYP3A4 inhibition or inactivation, leading to increased bioavailability or increased plasma drug levels and longer drug clearance times. Likewise, CYP3A4 induction or activation can lead to an increase in CYP3A4 activity, resulting in decreased bioavailability and loss of drug efficacy. The toxic effects of drugs can be caused by inhibition or increased expression of CYP3A4 through the formation of reactive metabolites. The use of combinations of drugs metabolized by CYP3A4 needs to be monitored carefully because it can cause adverse drug interactions.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank Sebelas Maret University for kind support during research.

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Received on 24.07.2022            Modified on 04.10.2022

Accepted on 01.12.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(6):3016-3024.

DOI: 10.52711/0974-360X.2023.00498