P450-mediated Drug-drug Interactions Research Articles

Clinically Significant Cytochrome P450-Mediated Drug-Drug Interactions in Children Admitted to Intensive Care Units.

Objectives Children admitted to intensive care units (ICUs) often require multiple medications due to the complexity and severity of their disease, which put them at an increased risk for drug interactions. This study examined cytochrome P450-mediated drug-drug interactions (DDIs) based on the Pediatric Intensive Care (PIC) database, with the aim of analyzing the incidence of clinically significant potential drug-drug interactions (pDDIs) and exploring the occurrence of actual adverse reactions. Methods The Lexicomp database was used to screen cytochrome P450-mediated DDI pairings with good levels of reliability and clear clinical phenotypes. Patients exposed to the above drug pairs during the same period were screened in the PIC database. The incidence of clinically significant pDDIs was calculated, and the occurrence of adverse reactions was explored based on laboratory measurements. Results In total, 84 (1.21%) of 6920 children who used two or more drugs were exposed to at least one clinically significant pDDI. All pDDIs were based on CYP3A4, with nifedipine + voriconazole (39.60%) being the most common drug pair, and the most frequent being the J02 class of drugs. Based on laboratory measurements, 15 adverse reactions were identified in 12 patients. Conclusions Clinically significant cytochrome P450-mediated pDDIs existed in the children admitted to ICUs, and some of the pDDIs led to adverse clinical outcomes. The use of clinical decision support systems can guide clinical medication use, and clinical monitoring of patients' needs has to be enhanced.

Prevalence of cytochrome P450-mediated potential drug-drug interactions in residents of intermediate care facilities for older adults in Japan.

Limited information is available on the prevalence of drug-drug interactions (DDI) in residents of long-term care facilities who often receive multiple drugs. This study aimed to evaluate the prevalence of clinically relevant cytochrome P450-mediated potential DDI in residents of intermediate care facilities for older adults (called Roken) in Japan. A nationwide drug utilization study was carried out for Roken residents in 2015 (up to five residents per facility). Potential DDI were identified with an explicit list of drugs that can be involved in clinically relevant cytochrome P450-mediated DDI in Japan. Logistic regression was used to evaluate the association of the number of drugs prescribed with the presence of potential DDI, adjusted for age, sex and long-term care needs level. The study included 1222 residents of 348 Roken who were prescribed two or more active drug substances. The participants who received ≥6 and ≥10 drugs represented 49% and 10% of total participants, respectively. In total, 42 two-drug combinations involving potential DDI were identified in 33 participants (2.7%) - benzodiazepines, proton pump inhibitors, calcium channel blockers and anti-epileptic drugs were frequently involved. The adjusted odds ratios for potential DDI were 2.84 (95% confidence interval 1.15-7.02) or 7.82 (95% confidence interval 2.96-20.70) in residents receiving six to nine drugs or ≥10 drugs, compared with those receiving two to five drugs. Approximately 3% of Roken residents were at risk for clinically relevant DDI. Reducing the number of drugs prescribed through medication reviews would mitigate the potential risk. Geriatr Gerontol Int 2019; 19: 513-517.

Identification of Cytochrome P450-Mediated Drug-Drug Interactions at Risk in Cases of Gene Polymorphisms by Using a Quantitative Prediction Model.

The magnitude of drug-drug interactions mediated by cytochrome P450 (CYP) may depend on the genotype of polymorphic cytochromes. The objective of this study was to identify drug-drug interactions with greater magnitude in CYP variant groups than in extensive metabolizers. The in-vivo mechanistic static model was used to predict the area under the curve ratio of drug-drug interactions. Five cytochromes (CYP3A4/5, 2D6, 2C9, 2C19, 1A2) and five groups of genotypes for each polymorphic cytochrome (CYP2D6, 2C9, 2C19) were considered. The area under the curve ratios were calculated for all combinations and all genotypes for 196 substrates and 96 inhibitors. Among the strongest interactions (area under the curve ratio greater than 5), two levels of gene sensitivity of drug-drug interactions were defined: the intermediate sensitivity, with a three- to five-fold stronger interaction in genotype groups other than in extensive metabolizers, and the high sensitivity, with a more than five-fold stronger interaction than in genotype groups other than extensive metabolizers. A red list of 104 interactions with a sensitivity greater than 3, involving 13 substrates and 24 interactors was obtained. There were 59 and 45 cases of high and intermediate sensitivity, respectively. The genotypes associated with a high sensitivity were CYP2D6 *3-8 *3-8 (sensitivity up to 24.3) and CYP2C19 *2-3*2-3 (sensitivity up to 37.8). A cytochrome polymorphism may lead to major drug-drug interactions in poor metabolizers, while these interactions may not be significant in extensive metabolizers. Among the 104 cases studied, the interaction could be of ca. 30-fold larger magnitude in the worst case. Genotyping of the patient and/or therapeutic drug monitoring of the substrate should be carried out when an association mentioned in the red list is prescribed. The concept of gene sensitivity of drug-drug interactions appears promising for the development of precision medicine.

Prevalence and Risk of Potential Cytochrome P450–Mediated Drug-Drug Interactions in Older Hospitalized Patients with Polypharmacy

As rates of polypharmacy rise and medication regimens become more complex, the risk of potential cytochrome P450 (CYP)-mediated drug-drug interactions (DDIs) is a growing clinical concern for older adults. To determine the prevalence of potential CYP-mediated DDIs in older hospitalized adults with polypharmacy and analyze the relationship between the number of drugs dispensed and the probability of these interactions in this high-risk population. A prospective 16-week cohort study was conducted among consecutive new patients aged 65 years and older with polypharmacy (>5 drugs) admitted to a community hospital. The medication profiles of these patients were analyzed with a new multidrug cytochrome-specific software program. The prevalence of potential CYP-mediated DDIs was determined, with the probability calculated as a function of the number of medications dispensed using multivariate Poisson regression adjusted for age and sex. Comparative performance of the software program and a standard 2-drug alert program for detecting these DDIs was evaluated using the Wilcoxon-Mann-Whitney rank-sum test. Pharmacists' decisions to recommend medication adjustment based on the probability of CYP-mediated DDIs were recorded. The prevalence of potential CYP-mediated DDIs detected among 275 older adults with polypharmacy was 80%. The probability of at least 1 CYP-mediated DDI was 50% for persons taking 5-9 drugs, 81% with 10-14 drugs, 92% with 15-19 drugs, and 100% with 20 or more drugs. Addition of each medication to a 5-drug regimen conferred a 12% increased risk of a potential CYP-mediated DDI after adjustment for age and sex (OR 1.12; 95% CI 1.09-1.14). The multidrug software identified a median increase of 3 (95% CI 2.5-3.5) potential CYP-mediated DDIs per patient, compared to use of the standard 2-drug alert software. Pharmacists targeted patients for medication adjustment or close clinical monitoring in 23% of cases. The prevalence of potential CYP-mediated DDIs is high in geriatric patients with polypharmacy. The risk of DDIs increases as a function of the number of medications dispensed. Pharmacists' decision to intervene for potential CYP-mediated DDIs depends on clinical judgment in addition to the output from drug alert software programs, but may be facilitated by a single multicomponent, multidrug potential CYP-mediated DDI assessment.

Enzyme kinetics of cytochrome P450-mediated reactions.

The most common drug-drug interactions may be understood in terms of alterations of metabolism, associated primarily with changes in the activity of cytochrome P450 (CYP) enzymes. Kinetic parameters such as Km, Vmax, Ki and Ka, which describe metabolism-based drug interactions, are usually determined by appropriate kinetic models and may be used to predict the pharmacokinetic consequences of exposure to one or multiple drugs. According to classic Michaelis-Menten (M-M) kinetics, one binding site models can be employed to simply interpret inhibition (pure competitive, non-competitive and uncompetitive) or activation of the enzyme. However, some cytochromes P450, in particular CYP3A4, exhibit unusual kinetic characteristics. In this instance, the changes in apparent kinetic constants in the presence of inhibitor or activator or second substrate do not obey the rules of M-M kinetics, and the resulting kinetics are not straightforward and hamper mechanistic interpretation of the interaction in question. These unusual kinetics include substrate activation (autoactivation), substrate inhibition, partial inhibition, activation, differential kinetics and others. To address this problem, several kinetic models can be proposed, based upon the assumption that multiple substrate binding sites exist at the active site of a particular P450, and the resulting kinetic constants are, therefore, solved to adequately describe the observed interaction between multiple drugs. The following is an overview of some cytochrome P450-mediated classic and atypical enzyme kinetics, and the associated kinetic models. Applications of these kinetic models can provide some new insights into the mechanism of P450-mediated drug-drug interactions.

Predictions of Cytochrome P450-Mediated Drug-Drug Interactions Using Cryopreserved Human Hepatocytes: Comparison of Plasma and Protein-Free Media Incubation Conditions

Cryopreserved human hepatocytes suspended in human plasma (HHSHP) have previously provided accurate CYP3A drug-drug interaction (DDI) predictions from a single IC(50) that captures both reversible and time-dependent inhibition. The goal of this study was to compare the accuracy of DDI predictions by a protein-free human hepatocyte system combined with the fraction unbound in plasma for inhibitor(s) with those obtained with protein-containing incubations. Seventeen CYP3A, CYP2C9, or CYP2D6 inhibitors were incubated with hepatocytes in human plasma or hepatocyte maintenance medium (HMM) for 20 min over a range of concentrations after which midazolam 1'-hydroxylation, diclofenac 4'-hydroxylation or (R)-bufuralol 1'-hydroxylation were used to quantify the corresponding cytochrome P450 (P450) catalytic activities. Two methods were used to predict the human exposure ratio of the victim drug in the presence and absence of inhibitor. The HMM K(i, app) values were combined with the free average systemic plasma concentration ("free [I] with HMM K(i, app)") and the plasma K(i, app) values were combined with the total average systemic plasma concentration ("total [I] with plasma K(i, app)"). Of 63 clinical DDI studies, the total [I] with plasma K(i, app) method predicted 89% of cases within 2-fold of the reported interaction whereas the free [I] with HMM K(i, app) method predicted only 59%. There was a general underprediction by the free [I] with HMM K(i, app) method, which is consistent with an underestimation of in vitro inhibition potency in this system. In conclusion, the HHSHP system proved to be a simple, accurate predictor of DDIs for three major P450s and superior to the protein-free approach.

Disposition and Drug-Drug Interaction Potential of Veliparib (ABT-888), a Novel and Potent Inhibitor of Poly(ADP-ribose) Polymerase

The disposition of veliparib [(R)-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide, ABT-888], a novel and potent inhibitor of poly(ADP-ribose) polymerase for the treatment of cancers, was investigated in rats and dogs after intravenous and oral administration of [(3)H]veliparib and compared with that of humans. Veliparib absorption was high. Dosed radioactivity was widely distributed in rat tissues. The majority of drug-related material was excreted in urine as unchanged drug (approximately 54, 41, and 70% of the dose in rats, dogs, and humans, respectively). A lactam M8 and an amino acid M3 were two major excretory metabolites in animals. In the circulation of animals and humans, veliparib was the major drug-related component, and M8 was one of the major metabolites. Monooxygenated metabolite M2 was significant in the rat and dog, and M3 was also significant in the dog. Veliparib biotransformation occurred on the pyrrolidine moiety via formation of a lactam, an amino acid, and an N-carbamoyl glucuronide, in addition to oxidation on benzoimidazole carboxamide and sequential glucuronidation. In vitro experiments using recombinant human cytochrome P450 (P450) enzymes identified CYP2D6 as the major enzyme metabolizing veliparib with minor contributions from CYP1A2, 2C19, and 3A4. Veliparib did not inhibit or induce the activities of major human P450s. Veliparib was a weak P-glycoprotein (P-gp) substrate, showing no P-gp inhibition. Taken together, these studies indicate a low potential for veliparib to cause clinically significant P-gp or P450-mediated drug-drug interactions (DDIs). Overall, the favorable dispositional and DDI profiles of veliparib should be beneficial to its safety and efficacy.

Review article: rifaximin, a minimally absorbed oral antibacterial, for the treatment of travellers’ diarrhoea

Travellers' diarrhoea, a common problem worldwide with significant medical impact, is generally treated with anti-diarrhoeal agents and fluid replacement. Systemic antibiotics are also used in selected cases, but these may be associated with adverse effects, bacterial resistance and drug-drug interactions. To review the clinical evidence supporting the efficacy and safety of the minimally absorbed oral antibiotic rifaximin in travellers' diarrhoea. PubMed and the Cochrane Register of Controlled Clinical Trials (to January 2010) and International Society of Travel Medicine congress abstracts (2003-2009) were searched to identify relevant publications. A total of 10 publications were included in the analysis. When administered three times daily for 3 days, rifaximin is superior to placebo or loperamide; it is at least as effective as ciprofloxacin in reducing duration of illness and restoring wellbeing in patients with travellers' diarrhoea, both with and without identification of a pathogen, as well as in diarrhoea caused by Escherichia coli infection. Rifaximin demonstrates only minimal potential for development of bacterial resistance and for cytochrome P450-mediated drug-drug interactions, and its tolerability profile is similar to that of placebo. When antibiotic therapy is warranted in uncomplicated travellers' diarrhoea, rifaximin may be considered as a first-line treatment option because of its favourable efficacy, tolerability and safety profiles.

Selection of Alternative CYP3A4 Probe Substrates for Clinical Drug Interaction Studies Using In Vitro Data and In Vivo Simulation

Understanding the potential for cytochrome P450-mediated drug-drug interactions (DDIs) is a critical step in the drug discovery process. DDIs of CYP3A4 are of particular importance because of the number of marketed drugs that are cleared by this enzyme. In response to studies that suggested the presence of several binding regions within the CYP3A4 active site, multiple probe substrates are often used for in vitro CYP3A4 DDI studies, including midazolam (the clinical standard), felodipine/nifedipine, and testosterone. However, the design of clinical CYP3A4 DDI studies may be confounded for cases such as 1-(2-hydroxy-2-methylpropyl)-N-[5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl]-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458), with which testosterone is predicted to exhibit a clinically relevant DDI whereas midazolam and felodipine/nifedipine are not. To develop an appropriate path forward for such clinical DDI studies, the inhibition potency of 20 known inhibitors of CYP3A4 were measured in vitro using 8 clinically relevant CYP3A4 probe substrates and testosterone. Hierarchical clustering suggested four probe substrate clusters: testosterone; felodipine; midazolam, buspirone, quinidine, and sildenafil; and simvastatin, budesonide, and fluticasone. The in vivo sensitivities of six clinically relevant CYP3A4 probe substrates (buspirone, cyclosporine, nifedipine, quinidine, sildenafil, and simvastatin) were determined in relation to midazolam from literature DDI data. Buspirone, sildenafil, and simvastatin exhibited similar or greater sensitivity than midazolam to CYP3A4 inhibition in vivo. Finally, Simcyp was used to predict the in vivo magnitude of CYP3A4 DDIs caused by AMG 458 using midazolam, sildenafil, simvastatin, and testosterone as probe substrates.

Mechanism of CYP2C9 Inhibition by Flavones and Flavonols

This article describes an in vitro investigation of the inhibition of cytochrome P450 (P450) 2C9 by a series of flavonoids made up of flavones (flavone, 6-hydroxyflavone, 7-hydroxyflavone, chrysin, baicalein, apigenin, luteolin, scutellarein, and wogonin) and flavonols (galangin, fisetin, kaempferol, morin, and quercetin). With the exception of flavone, all flavonoids were shown to inhibit CYP2C9-mediated diclofenac 4'-hydroxylation in the CYP2C9 RECO system, with K(i) value <or= 2.2 microM. In terms of the mechanism of inhibition, 6-hydroxyflavone was found to be a noncompetitive inhibitor of CYP2C9, whereas the other flavonoids were competitive inhibitors. Computer docking simulation and constructed mutants substituted at residue 100 of CYP2C9.1 indicate that the noncompetitive binding site of 6-hydroxyflavone lies beside Phe100, similar to the reported allosteric binding site of warfarin. The other flavonoids exert competitive inhibition through interaction with the substrate binding site of CYP2C9 accessed by flurbiprofen. These results suggest flavonoids can participate in interactions with drugs that act as substrates for CYP2C9 and provide a possible molecular basis for understanding cooperativity in human P450-mediated drug-drug interactions.

Integrated in Vitro Analysis for the in Vivo Prediction of Cytochrome P450-Mediated Drug-Drug Interactions

Unbound IC(50) (IC(50,u)) values of 15 drugs were determined in eight recombinantly expressed human cytochromes P450 (P450s) and human hepatocytes, and the data were used to simulate clinical area under the plasma concentration-time curve changes (deltaAUC) on coadministration with prototypic CYP2D6 substrates. Significant differences in IC(50,u) values between enzyme sources were observed for quinidine (0.02 microM in recombinant CYP2D6 versus 0.5 microM in hepatocytes) and propafenone (0.02 versus 4.1 microM). The relative contribution of individual P450s toward the oxidative metabolism of clinical probes desipramine, imipramine, tolterodine, propranolol, and metoprolol was estimated via determinations of intrinsic clearance using recombinant P450s (rP450s). Simulated deltaAUC were compared with those observed in vivo via the ratios of unbound inhibitor concentration at the entrance to the liver to inhibition constants determined against rP450s ([I](in,u)/K(i)) and incorporating parallel substrate elimination pathways. For this dataset, there were 20% false negatives (observed deltaAUC >or= 2, predicted deltaAUC < 2), 77% correct predictions, and 3% false positives. Thus, the [I](in,u)/K(i) approach appears relatively successful at estimating the degree of clinical interactions and can be incorporated into drug discovery strategies. Using a Simcyp ADME (absorption, metabolism, distribution, elimination) simulator (Simcyp Ltd., Sheffield, UK), there were 3% false negatives, 94% correct simulations, and 3% false positives. False-negative predictions were rationalized as a result of mechanism-based inhibition, production of inhibitory metabolites, and/or hepatic uptake. Integrating inhibition and reaction phenotyping data from automated rP450 screens have shown applicability to predict the occurrence and degree of in vivo drug-drug interactions, and such data may identify the clinical consequences for candidate drugs as both "perpetrators" and "victims" of P450-mediated interactions.

Understanding Cooperativity in Human P450 Mediated Drug-Drug Interactions

Multiple drugs can interact, often leading to adverse side effects. One well documented site for these interactions includes the group of cytochrome P450 monoxygenases. Several human hepatic systems are known to bind more than a single substrate molecule which can give rise to the terms “homotropic and heterotopic cooperativity” to define the resultant thermodynamic and kinetic properties observed in drug metabolism investigations. We provide a means for understanding and quantitating these drug-drug interactions by documenting the functional properties of the various states of the enzyme and show that, even in the absence of true binding cooperativity, significant non-Michaelis metabolic profiles are possible.

INVESTIGATION OF DRUG-DRUG INTERACTION POTENTIAL OF BORTEZOMIB IN VIVO IN FEMALE SPRAGUE-DAWLEY RATS AND IN VITRO IN HUMAN LIVER MICROSOMES

Bortezomib (Velcade, PS-341), a dipeptidyl boronic acid, is a first-in-class proteasome inhibitor approved in 2003 for the treatment of multiple myeloma. In a preclinical toxicology study, bortezomib-treated rats resulted in liver enlargement (35%). Ex vivo analyses of the liver samples showed an 18% decrease in cytochrome P450 (P450) content, a 60% increase in palmitoyl coenzyme A beta-oxidation activity, and a 41 and 23% decrease in CYP3A protein expression and activity, respectively. Furthermore, liver samples of bortezomib-treated rats had little change in CYP2B and CYP4A protein levels and activities. To address the likelihood of clinical drug-drug interactions, the P450 inhibition potential of bortezomib and its major deboronated metabolites M1 and M2 and their dealkylated metabolites M3 and M4 was evaluated in human liver microsomes for the major P450 isoforms 1A2, 2C9, 2C19, 2D6, and 3A4/5. Bortezomib, M1, and M2 were found to be mild inhibitors of CYP2C19 (IC(50) approximately 18.0, 10.0, and 13.2 microM, respectively), and M1 was also a mild inhibitor of CYP2C9 (IC(50) approximately 11.5 microM). However, bortezomib, M1, M2, M3, and M4 did not inhibit other P450s (IC(50) values > 30 microM). There also was no time-dependent inhibition of CYP3A4/5 by bortezomib or its major metabolites. Based on these results, no major P450-mediated clinical drug-drug interactions are anticipated for bortezomib or its major metabolites. To our knowledge, this is the first report on P450-mediated drug-drug interaction potential of proteasome inhibitors or boronic acid containing therapeutics.

Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update.

The selective serotonin reuptake inhibitors (SSRIs) have become the most prescribed antidepressants in many countries. Although the SSRIs share a common mechanism of action, they differ substantially in their chemical structure, metabolism, and pharmacokinetics. Perhaps the most important difference between the SSRIs is their potential to cause drug-drug interactions through inhibition of cytochrome-P450 (CYP) isoforms. This paper provides an update on both the in vitro and in vivo evidence with respect to CYP-mediated drug-drug interactions with this class of antidepressants. The available evidence clearly indicates that the individual SSRIs display a distinct profile of cytochrome P450 inhibition. Fluvoxamine is a potent CYP1A2 and CYP2C19 inhibitor, and a moderate CYP2C9, CYP2D6, and CYP3A4 inhibitor. Fluoxetine and paroxetine are potent CYP2D6 inhibitors, whereas fluoxetine's main metabolite, norfluoxetine, has a moderate inhibitory effect on CYP3A4. Sertraline is a moderate CYP2D6 inhibitor; citalopram appears to have little effect on the major CYP isoforms. Fluoxetine deserves special attention as inhibitory effects on CYP-activity can persist for several weeks after fluoxetine discontinuation because of the long half-life of fluoxetine and its metabolite norfluoxetine. Drug combinations with SSRIs should be assessed on an individual basis. Knowledge regarding the CYP-isoforms involved in the metabolism of the co-administered drug may help clinicians to anticipate and avoid potentially dangerous drug-drug interactions. Anticipated interactions can usually be managed by appropriate dose adjustment and titration of the object drug. In some cases, therapeutic drug monitoring can be useful. Equally well, an SSRI with limited interaction potential may be selected to treat depression in patients that receive other medications.