Important Drug-drug Interactions Research Articles

Validation of a bupropion, dextromethorphan, and omeprazole cocktail for simultaneous phenotyping of cytochrome P450 2B11, 2D15, and 3A12 activities in dogs.

Develop a cytochrome P450 (CYP) phenotyping cocktail for dogs using specific substrates for hepatic P450 enzymes CYP2B11, CYP2D15, and CYP3A12 and determine whether alternative sampling methods (saliva and urine) or single time point samples could be used instead of multiple blood sampling. 12 healthy client-owned dogs (8 females and 4 males) from February 2019 to May 2019. In a randomized crossover study, dogs received oral administration of the probe drug bupropion (75 mg), dextromethorphan (30 mg), or omeprazole (40 mg) alone or as a 3-drug combination (Program in Individualized Medicine [PrIMe] cocktail) to evaluate simultaneous phenotyping of CYP2B11, CYP2D15, and CYP3A12. Pharmacokinetic profiles for the probe drugs and metabolites were determined using plasma, saliva, and urine. Dogs received probe drugs alone or combined. Pharmacokinetic profiles up to 6 hours postdose for the probe drugs and metabolites were determined using plasma, saliva, and urine. The PrIMe cocktail was well tolerated. There was no statistically significant interaction between the probe drugs when administered together. Single time point plasma metabolic ratios at 4 hours postdose for all probe drugs strongly correlated with the corresponding area under the plasma concentration-versus-time curve (AUC) ratios. Saliva AUC metabolic ratios for CYP3A12 and CYP2D15 and 6-hour urine for CYP2B11 and CYP2D15 were correlated with plasma AUC ratios. The PrIMe cocktail can be used for simultaneous CYP phenotyping using plasma 4-hour single time point sample metabolic ratios. Saliva and urine sampling are suitable for specific CYPs. The PrIMe cocktail has potential as a useful tool in dogs to detect clinically important CYP-mediated drug-drug interactions, identify novel pharmacogenes, determine the drug-metabolizing phenotype of individual dogs, aid in individualized dose selection, and evaluate the effects of various physiological states on drug metabolism.

Pathophysiology and Clinical Management of Dyslipidemia in People Living with HIV: Sailing through Rough Seas.

Infections with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) represent one of the greatest health burdens worldwide. The complex pathophysiological pathways that link highly active antiretroviral therapy (HAART) and HIV infection per se with dyslipidemia make the management of lipid disorders and the subsequent increase in cardiovascular risk essential for the treatment of people living with HIV (PLHIV). Amongst HAART regimens, darunavir and atazanavir, tenofovir disoproxil fumarate, nevirapine, rilpivirine, and especially integrase inhibitors have demonstrated the most favorable lipid profile, emerging as sustainable options in HAART substitution. To this day, statins remain the cornerstone pharmacotherapy for dyslipidemia in PLHIV, although important drug-drug interactions with different HAART agents should be taken into account upon treatment initiation. For those intolerant or not meeting therapeutic goals, the addition of ezetimibe, PCSK9, bempedoic acid, fibrates, or fish oils should also be considered. This review summarizes the current literature on the multifactorial etiology and intricate pathophysiology of hyperlipidemia in PLHIV, with an emphasis on the role of different HAART agents, while also providing valuable insights into potential switching strategies and therapeutic options.

On the Possible Effect of Phytic Acid (Myo-Inositol Hexaphosphoric Acid, IP6) on Cytochromes P450 and Systems of Xenobiotic Metabolism in Different Hepatic Models.

As compounds of natural origin enter human body, it is necessary to investigate their possible interactions with the metabolism of drugs and xenobiotics in general, namely with the cytochrome P450 (CYP) system. Phytic acid (myo-inositol hexaphosphoric acid, IP6) is mainly present in plants but is also an endogenous compound present in mammalian cells and tissues. It has been shown to exhibit protective effect in many pathological conditions. For this paper, its interaction with CYPs was studied using human liver microsomes, primary human hepatocytes, the HepG2 cell line, and molecular docking. Docking experiments and absorption spectra demonstrated the weak ability of IP6 to interact in the heme active site of CYP1A. Molecular docking suggested that IP6 preferentially binds to the protein surface, whereas binding to the active site of CYP1A2 was found to be less probable. Subsequently, we investigated the ability of IP6 to modulate the metabolism of xenobiotics for both the mRNA expression and enzymatic activity of CYP1A enzymes. Our findings revealed that IP6 can slightly modulate the mRNA levels and enzyme activity of CYP1A. However, thanks to the relatively weak interactions of IP6 with CYPs, the chances of the mechanisms of clinically important drug-drug interactions involving IP6 are low.

Drug-drug interactions and the risk of adverse drug reaction-related hospital admissions in the older population.

The aims of this study were to estimate potentially clinically important drug-drug interaction (DDI) prevalence, and the average causal effect of DDI exposure on adverse drug reaction (ADR)-related hospital admission, and to examine differences in health-related quality of life (HRQoL) and length of stay (LOS) per DDI exposure in an older (≥65 years) population acutely hospitalized. This was a cross-sectional study conducted among 798 older individuals acutely admitted to hospital in Ireland between 2016 and 2017. Medication (current/recently discontinued/over-the-counter) and clinical data (e.g., creatinine clearance) were available. DDIs were identified using the British National Formulary (BNF) and Stockley's Drug Interactions. Causal inference models for DDI exposure on ADR-related hospital admission were developed using directed acyclic graphs. Multivariable logistic regression was used to estimate the average causal effect. Differences in HRQoL (EQ-5D) and LOS per DDI exposure were examined non-parametrically. DDI prevalence, adjusted odds ratios (aOR), and 95% confidence intervals (CIs) are reported. A total of 782 (98.0%) individuals using two or more drugs were included. Mean age was 80.9 (SD ± 7.5) years (range: 66-105); 52.2% were female; and 45.1% (n = 353) had an ADR-related admission. At admission, 316 (40.4% [95% CI: 37.0-43.9]) patients had at least one DDI. The average causal effect of DDI exposure on ADR-related hospital admission was aOR = 1.21 [95% CI: 0.89-1.64]. This was significantly increased by exposure to: DDIs which increase bleeding risk (aOR = 2.00 [1.26-3.12]); aspirin-warfarin (aOR = 2.78 [1.37-5.65]); and esomeprazole-escitalopram (aOR = 3.22 [1.13-10.25]. DDI-exposed patients had lower HRQoL (mean EQ-5D = 0.49 [±0.39]) compared those non-DDI-exposed (mean EQ-5D = 0.57 [±0.41]), (P = .03); and greater median LOS in hospital (8 [IQR5-16]days) compared those non-DDI-exposed (7 [IQR 4-14] days),(P = .04). Potentially clinically important DDIs carry an increased average causal effect on ADR-related admission, significantly (two-fold) by exposure to DDIs that increase bleeding risk, which should be targeted for medicine optimization.

Potential drug-drug interactions in a multi-center study of death cases of COVID-19: The significance of appropriate drug choice.

The prevalence, types, severity, risk ratings, and common pairs of involved drugs, and the most important potential drug-drug interactions (pDDIs) in coronavirus disease 2019 (-COVID-19) deceased cases were evaluated. We reviewed the medical records of 157 confirmed COVID-19 deceased cases hospitalized in 27 province-wide hospitals. Patients' demographics and clinical data (including comorbidities, vital signs, length of in-hospital survival, electrocardiograms (ECGs), medications, and lab test results) were extracted. The online Lexi-interact database and Stockley's drug interactions reference were used to detect pDDIs retrospectively. The QTc interval and total Tisdale risk score were also calculated. Descriptive analysis, analysis of variance, Fisher exact test, and multivariate analysis were conducted for data analysis. Of 157 study cases, 63% were male, had a mean age of 68 years, and 55.7% had one or more underlying diseases. All patients had polypharmacy, with 69.2% having ≥15 drugs/day. We detected 2,416 pDDIs in patients' records, of which 658 (27.2%) were interactions with COVID drugs. Lopinavir/ritonavir among -COVID drugs and fentanyl among non-COVID drugs were commonly involved in the interactions. pDDIs was significantly higher in the polypharmacy group of ≥15 medications (p<0.001). A majority (83%) had received drug(s) with the QTc prolongation effect, of whom 67% had actual QTc prolongations in their ECGs. The regression analysis showed that by increasing 6.7% in polypharmacy, one day increase in-hospital survival can be expected. Moreover, an increase of 2.3% in white blood cells or 10.5% in serum potassium level decreased in-hospital survival by 1%. The findings underscored the importance of careful drug choice, especially in the hectic search for early treatments in pandemics of novel diseases. Close monitoring of patients' drug choice is warranted for reducing pDDIs and their adverse effects in any new disease outbreak.

What clindamycin dose should be administered by continuous infusion during combination therapy with rifampicin? A prospective population pharmacokinetics study.

Despite its important drug-drug interaction, combined clindamycin/rifampicin therapy may achieve effective plasma clindamycin concentrations, provided clindamycin is administered by continuous infusion. However, the precise clindamycin dose remains unknown. This study was undertaken to determine the daily clindamycin dose to be administered by continuous infusion in combination with rifampicin to achieve effective plasma clindamycin concentrations. Two plasma clindamycin concentrations were determined prospectively for 124 patients with bone-and-joint infections treated with continuously infused clindamycin. Twenty patients received clindamycin monotherapy, 19 clindamycin combined with rifampicin and 85 received clindamycin successively without and with rifampicin. A population pharmacokinetic model was developed using NONMEM 7.5. Monte Carlo simulations were run to determine which regimens obtained clindamycin concentrations of at least 3 mg/L. A linear one-compartment model with first-order elimination accurately described the data. Clindamycin distribution volume was not estimated. Mean clindamycin clearances with rifampicin and without, respectively, were 33.6 and 10.9 L/h, with 12.8% interindividual variability. The lowest daily clindamycin dose achieving plasma concentrations of at least 3 mg/L in >90% of the patients, when combined with rifampicin, was 4200 mg/24 h. Our results support continuous infusion of 4200 mg of clindamycin/24 h, in combination with rifampicin. This high-dose regimen requires therapeutic drug monitoring-guided dose adaptation.

Mechanisms and Clinical Significance of Pharmacokinetic Drug Interactions Mediated by FDA and EMA-approved Hepatitis C Direct-Acting Antiviral Agents.

The treatment of patients infected with the hepatitis C virus (HCV) has been revolutionised by the development of direct-acting antiviral agents (DAAs) that target specific HCV proteins involved in viral replication. The first DAAs were associated with clinical problems such as adverse drug reactions and pharmacokinetic drug-drug interactions (DDIs). Current FDA/EMA-approved treatments are combinations of DAAs that simultaneously target the HCV N5A-protein, the HCV N5B-polymerase and the HCV NS3/4A-protease. Adverse events and DDIs are less likely with these DAA combinations but several DDIs of potential clinical significance remain. Much of the available information on the interaction of DAAs with CYP drug-metabolising enzymes and influx and efflux transporters is contained in regulatory summaries and is focused on DDIs of likely clinical importance. Important DDIs perpetrated by current DAAs include increases in the pharmacokinetic exposure to statins and dabigatran. Some mechanistic information can be deduced. Although the free concentrations of DAAs in serum are very low, a number of these DDIs are likely mediated by the inhibition of systemic influx transporters, especially OATP1B1/1B3. Other DDIs may arise by DAA-mediated inhibition of intestinal efflux transporters, which increases the systemic concentrations of some coadministered drugs. Conversely, DAAs are victims of DDIs mediated by cyclosporin, ketoconazole, omeprazole and HIV antiretroviral drug combinations, especially when boosted by ritonavir and, to a lesser extent, cobicistat. In addition, concurrent administration of inducers, such as rifampicin, carbamazepine and efavirenz, decreases exposure to some DAAs. Drug-drug interactions that increase the accumulation of HCV N3/4A-protease inhibitors like grazoprevir may exacerbate hepatic injury in HCV patients.

Antibiotics and Lipid-Modifying Agents: Potential Drug-Drug Interactions and Their Clinical Implications.

Evidence-based prescribing requires taking into consideration the many aspects of optimal drug administration (e.g., dosage, comorbidities, co-administered drugs, etc.). A key issue is the administration of drugs for acute disorders that may potentially interfere with previously prescribed long-term medications. Initiating an antibiotic for an acute bacterial infection constitutes a common example. Hence, appropriate knowledge and awareness of the potential DDIs of antibiotics would lead to proper adjustments, thus preventing over- or under-treatment. For example, some statins, which are the most prescribed lipid-modifying agent (LMA), can lead to clinically important drug-drug interactions (DDIs) with the concurrent administration of antibiotics, e.g., macrolides. This review discusses the clinically significant DDIs of antibiotics associated with co-administrated lipid-lowering therapy and highlights common cases where regimen modifications may or may not be necessary.

An update on drug-drug interactions for care of the acutely ill in the era of COVID-19.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. To provide key pharmacological concepts underlying drug-drug interactions (DDIs), a decision-making framework, and a list of DDIs that should be considered in the context of contemporary acutely ill patients with COVID-19. DDIs are frequently encountered in the acutely ill. The implications of DDIs include either increased risk of drug toxicity or decreased effectiveness, which may have severe consequences in the acutely ill due to lower physiological and neurocognitive reserves in these patients. In addition, an array of additional therapies and drug classes have been used for COVID-19 that were not typically used in the acute care setting. In this update on DDIs in the acutely ill, we provide key pharmacological concepts underlying DDIs, including a discussion of the gastric environment, the cytochrome P-450 (CYP) isozyme system, transporters, and pharmacodynamics in relation to DDIs. We also provide a decision-making framework that elucidates the identification of DDIs, risk assessment, selection of alternative therapies, and monitoring. Finally, important DDIs pertaining to contemporary acute care clinical practice related to COVID-19 are discussed. Interpreting and managing DDIs should follow a pharmacologically based approach and a systematic decision-making process to optimize patient outcomes.

Assessing Medication Use Quality in Older Outpatients Using the Beers Criteria: Findings from a Single-Center Retrospective Study.

No comprehensive assessment of the quality of medications used in older outpatients has been conducted in Thailand. This study aimed to ascertain the prevalence of and factors contributing to older outpatients&apos; use of potentially inappropriate medications (PIMs). This cross-sectional study retrospectively assessed the prescriptions of older (≥60 years) outpatients at a secondary-care hospital. For PIM identification, the 2019 American Geriatric Society (AGS) Beers criteria were applied, considering all five PIM categories: PIM category I (medications that are potentially inappropriate in most older adults), II (disease-/syndrome-exacerbating drugs), III (medications that should be used with caution), IV (clinically important drug-drug interactions), and V (medications that should be avoided or have their dosage reduced based on renal function). This study included 22,099 patients (mean age, 68.86±7.64 years). Nearly three-fourths of patients were prescribed PIMs, with 68.90%, 7.68%, 44.23%, 15.66%, and 3.05%, respectively, receiving category I-V medications. The positive factors associated with PIM use included female sex (odds ratio [OR]=1.08; 95% confidence interval [CI], 1.01-1.16), age ≥75 years (OR=1.10; 95% CI, 1.01-1.21), polypharmacy (OR=10.21; 95% CI, 9.31-11.21), ≥3 diagnostic categories (OR=2.31; 95% CI, 2.14-2.50), and ≥3 chronic morbidities (OR=1.46; 95% CI, 1.26-1.68). The negative factor associated with PIM use was a comorbidity score of ≥1 (OR=0.78; 95% CI, 0.71-0.86). PIM use among older outpatients remains highly prevalent in clinical practice. The results of this study identified polypharmacy as the strongest factor affecting PIM use.

Evaluation of the Potentially Inappropriate Cardiovascular Medication Prescription in Elderly: A Nationwide Study in Turkey.

Elderly comprises a specific group due to possible alterations in the effects of drugs and comorbidities. We aimed to identify for the first time the characteristics and rates regarding the inappropriate prescriptions of cardiovascular system medications in the geriatric age group in Turkey. Cardiovascular system medications prescribed electronically by family physicians to patients aged 65 and over, in the years 2015 and 2016, were obtained through Prescription Information System administered by the Ministry of Health. Evaluation of potentially inappropriate prescriptions was done according to the 'Beers Criteria 2015 update.' Prescription rates for each group were evaluated under sub-breakdowns for the specialty of family physicians, gender, age groups, and 'Nomenclature of Territorial Units for Statistics' regions. Approximately 65 million prescriptions were evaluated. The rate of potentially inappropriate cardiovascular medication prescribing was 0.33%. This raised to 11.56% when 'drugs to be used with caution' were included. It was observed that potentially inappropriate drugs have been prescribed more by specialist family physicians. The most frequently prescribed potentially inappropriate drugs were doxazosin in the diagnosis of hypertension and methyldopa regardless of indication. Diclofenac-warfarin was the most commonly prescribed concomitant drug use in the potentially clinically important drug-drug interactions group. The rate of potentially inappropriate drug prescribing was higher in males and in aged 80 years and older. This pharmacoepidemiological study draws attention to potentially inappropriate cardiovascular system drugs prescribed in primary care settings to the elderly. The rate of potentially inappropriate cardiovascular system drug prescribed was found to be very low in Turkey.

Evaluation of potential drug-drug interactions and polypharmacy in hospitalized COVID-19 patients.

Drugs that are used in COVID-19 infection, may interact with each other, as well as with the drugs for comorbidities, used concomitantly with COVID-19 treatment. It is quite important to calculate and present the patients' exposure to clinically important potential drug-drug interactions (pDDIs). We aimed to investigate the pDDIs and the burden of polypharmacy in COVID-19. The medical records of 126 consecutive inpatients with COVID-19 treatment were retrospectively analyzed. The Lexi-interact database was used to investigate pDDIs. According to the Lexi-interact database, 605 pDDIs were detected. Of these pDDIs, 23 (3.8%) were A risk category interaction, 186 (30.7%) were B risk category interaction, 339 (56%) were C risk category interaction, 54 (8.9%) were D risk category interaction, and 3 (0.5%) were X risk category interaction. Sixty-five-point five percent of pDDIs (n=396) were clinically important pDDIs (C, D, and X categories), and 69 patients (54.8%) had at least one clinically important pDDIs. The most interacting drug was hydroxychloroquine (n=171, 28.3%). Hydroxychloroquine was also the most interacting drug in the C risk category (n=101, 29.8%) and had 19 pDDIs with metformin, 16 pDDIs with beta-blockers, 13 pDDIs with acetylsalicylic acid, and 10 pDDIs with insulin in the C risk category. Enoxaparin was the most interacting drug (n=25, 46.3%) in the D risk category and most of them were with acetylsalicylic acid (n=12). The most common possible clinical manifestations of pDDIs were QT prolongation, hypoglycemia, and hemorrhage. One hundred and eighteen patients (93.6%) used five or more drugs daily. There was a significant positive correlation between the number of drugs prescribed to patients and the number of clinically important pDDIs (r=0.80, p<0.001). Clinically important pDDIs are common among COVID-19 patients and the majority of pDDIs require monitoring of therapy. COVID-19 patients should be closely observed for QT prolongation, hypoglycemia, and hemorrhage due to pDDIs during treatment.

Deconstructing the Dogma: Systematic Literature Review and Meta-analysis of Adjunctive Gentamicin and Rifampin in Staphylococcal Prosthetic Valve Endocarditis.

Based primarily on in vitro and animal models, with little data directly addressing patient outcomes, current guidelines recommend treating staphylococcal prosthetic valve endocarditis (PVE) with antibiotic combinations including gentamicin and rifampin. Here, we synthesize the clinical data on adjunctive rifampin and gentamicin in staphylococcal PVE. We conducted a systematic review and meta-analysis of PubMed- and Cochrane-indexed studies reporting outcomes of staphylococcal PVE treated with adjunctive rifampin, gentamicin, both agents, or neither (ie, glycopeptide or β-lactam monotherapy). We recorded outcomes including mortality, relapsed infection, length of stay, nephrotoxicity, hepatotoxicity, and important drug-drug interactions (DDIs). Four relevant studies were identified. Two studies (n = 117) suggested that adding gentamicin to rifampin-containing regimens did not reduce clinical failure (odds ratio [OR], 0.98 [95% confidence interval {CI}, .39-2.46]), and 2 studies (n = 201) suggested that adding rifampin to gentamicin-containing regimens did not reduce clinical failure (OR, 1.29 [95% CI, .71-2.33]). Neither gentamicin nor rifampin was associated with reduced infection relapse; 1 study found that rifampin treatment was associated with longer hospitalizations (mean, 31.3 vs 42.3 days; P < .001). Comparative safety outcomes were rarely reported, but 1 study found rifampin to be associated with hepatoxicity, nephrotoxicity, and DDIs, leading to treatment discontinuation in 31% of patients. The existing clinical data do not suggest a benefit of either adjunctive gentamicin or rifampin in staphylococcal PVE. Given that other studies also suggest these agents add nephrotoxicity, hepatoxicity, and risk of DDIs without benefit in staphylococcal endovascular infections, we suggest that recommendations for gentamicin and rifampin in PVE be downgraded and primarily be used within the context of clinical trials.

Reimagining the Framework Supporting the Static Analysis of Transporter Drug Interaction Risk; Integrated Use of Biomarkers to Generate Pan-Transporter Inhibition Signatures.

Solute carrier (SLC) transporters present as the loci of important drug-drug interactions (DDIs). Therefore, sponsors generate in vitro half-maximal inhibitory concentration (IC50 ) data and apply regulatory agency-guided "static" methods to assess DDI risk and the need for a formal clinical DDI study. Because such methods are conservative and high false-positive rates are likely (e.g., DDI study triggered when liver SLC R value ≥ 1.04 and renal SLC maximal unbound plasma (Cmax,u )/IC50 ratio ≥ 0.02), investigators have attempted to deploy plasma- and urine-based SLC biomarkers in phase I studies to de-risk DDI and obviate the need for drug probe-based studies. In this regard, it was possible to generate in-house in vitro SLC IC50 data for various clinically (biomarker)-qualified perpetrator drugs, under standard assay conditions, and then estimate "% inhibition" for each SLC and relate it empirically to published clinical biomarker data (area under the plasma concentration vs. time curve (AUC) ratio (AUCR, AUCinhibitor /AUCreference ) and % decrease in renal clearance (ΔCLrenal )). After such a "calibration" exercise, it was determined that only compounds with high R values (> 1.5) and Cmax,u /IC50 ratios (> 0.5) are likely to significantly modulate liver (AUCR > 1.25) and renal (ΔCLrenal > 25%) biomarkers and evoke DDI risk. The % inhibition approach supports integration of liver and renal SLC data and allows one to generate pan-SLC inhibition signatures for different test perpetrators (e.g., SLC % inhibition ranking). In turn, such signatures can guide the selection of the most appropriate individual (or combinations of) biomarkers for testing in phase I studies.

Clinically Relevant Interactions Between Ritonavir-Boosted Nirmatrelvir and Concomitant Antiseizure Medications: Implications for the Management of COVID-19 in Patients with Epilepsy

Ritonavir-boosted nirmatrelvir (RBN) has been authorized recently in several countries as an orally active anti-SARS-CoV-2 treatment for patients at high risk of progressing to severe COVID-19 disease. Nirmatrelvir is the active component against the SARS-CoV-2 virus, whereas ritonavir, a potent CYP3A inhibitor, is intended to boost the activity of nirmatrelvir by increasing its concentration in plasma to ensure persistence of antiviral concentrations during the 12-hour dosing interval. RBN is involved in many clinically important drug–drug interactions both as perpetrator and as victim, which can complicate its use in patients treated with antiseizure medications (ASMs). Interactions between RBN and ASMs are bidirectional. As perpetrator, RBN may increase the plasma concentration of a number of ASMs that are CYP3A4 substrates, possibly leading to toxicity. As victims, both nirmatrelvir and ritonavir are subject to metabolic induction by concomitant treatment with potent enzyme-inducing ASMs (carbamazepine, phenytoin, phenobarbital and primidone). According to US and European prescribing information, treatment with these ASMs is a contraindication to the use of RBN. Although remdesivir is a valuable alternative to RBN, it may not be readily accessible in some settings due to cost and/or need for intravenous administration. If remdesivir is not an appropriate option, either bebtelovimab or molnupiravir may be considered. However, evidence about the clinical efficacy of bebtelovimab is still limited, and molnupiravir, the only orally active alternative, is deemed to have appreciably lower efficacy than RBN and remdesivir.

Comparing Important and Well-documented Potential Drug-Drug Interactions between Emergency, Medical, and Surgical ICUs of a Respiratory Referral Center.

IntroductionDrug–drug interaction (DDI) is one of the major healthcare challenges in intensive care units (ICUs). The prevalence of DDIs and interacting drug pairs may vary between different types of ICUs. This study aimed to compare the frequency and nature of important and well-documented potential DDIs (pDDIs) in three types of ICUs.Materials and methodsA prospective study was conducted in medical (M), surgical (S), and emergency (E) ICUs of a tertiary referral center for respiratory diseases. A pharmacist checked the patients’ files three days in a week for 6 months. The pDDIs were identified using the Lexi-Interact database. Interactions with a severity rating of D (modify regimen) and X (avoid combination) and with a reliability rating of good and excellent were considered important and well-documented. These pDDIs were evaluated in terms of drug combinations, mechanisms of interaction, and clinical management.ResultsOne hundred eighty-nine patients admitted to MICU, SICU, and EICU were included in the study. The percentage of patients who experienced at least one important and well-documented pDDI was 18.8% in MICU, 11.1% in SICU, and 11.8% in EICU. The most common drug pairs causing important and well-documented interactions were atracurium + hydrocortisone in MICU, meropenem + valproic acid in MICU and EICU, and aspirin + warfarin in SICU.ConclusionThe current study shows different frequency and nature of pDDIs between three types of ICUs. We recommend conducting similar studies in other settings to develop evidence-based guidance on clinically relevant pDDIs in different types of ICUs.How to cite this articleHosseinpoor Z, Farzanegan B, Baniasadi S. Comparing Important and Well-documented Potential Drug–Drug Interactions between Emergency, Medical, and Surgical ICUs of a Respiratory Referral Center. Indian J Crit Care Med 2022;26(5):574–578.

Stereoselective Metabolism of Bupropion to Active Metabolites in Cellular Fractions of Human Liver and Intestine.

Striking stereoselective disposition of the antidepressant and smoking cessation aid bupropion (BUP) and its active metabolites observed clinically influence patients' response to BUP therapy and its clinically important drug-drug interactions (DDI) with CYP2D6 substrates. However, understanding of the biochemical mechanisms responsible is incomplete. This study comprehensively examined hepatic and extrahepatic stereoselective metabolism of BUP in vitro Racemic-, R-, and S-BUP were incubated separately with pooled cellular fractions of human liver [microsomes (HLMs), S9 fractions (HLS9s), and cytosols (HLCs)] and intestinal [microsomes (HIMs), S9 fractions (HIS9s), and cytosols (HICs)] and cofactors. Formations of diastereomers of 4-hydroxyBUP (OHBUP), threohydroBUP (THBUP), and erythrohydroBUP (EHBUP) were quantified using a novel chiral ultra-high performance liquid chromatography/tandem mass spectrometry method. Racemic BUP (but not R- or S-BUP) was found suitable to determine stereoselective metabolism of BUP; both enantiomers showed complete racemization. Compared with that of RR-THBUP, the in vitro intrinsic clearance (Clint) for the formation of SS-THBUP was 42-, 19-, and 8.3-fold higher in HLMs, HLS9 fractions, and HLCs, respectively; Clint for the formation of SS-OHBUP and RS-EHBUP was also higher (2.7- to 3.9-fold) than their R-derived counterparts. In cellular fractions of human intestine, ≥ 95% of total reduction was accounted by the formation of RR-THBUP. Ours is the first to demonstrate marked stereoselective reduction of BUP in HLCs, HIMs, HIS9 fractions, and HICs, providing the first evidence for tissue- and cellular fraction-dependent stereoselective metabolism of BUP. These data may serve as the first critical step toward understanding factors dictating BUP's stereoselective disposition, effects, and DDI risks. SIGNIFICANCE STATEMENT: This work provides a deeper insight into bupropion (BUP) stereoselective oxidation and reduction to active metabolites in cellular fractions of human liver and intestine tissues. The results demonstrate tissue- and cellular fraction-dependent stereospecific metabolism of BUP. These data may improve prediction of BUP stereoselective disposition and understanding of BUP's effects and CYP2D6-dependent drug-drug interaction in vivo.

Potential for Drug Interactions and Polypharmacy From Treatment of COVID-19 in Long-Term Care

Potential for Drug Interactions and Polypharmacy From Treatment of COVID-19 in Long-Term Care

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Background:Schizophrenia (SCZ) and rheumatoid arthritis (RA) may remain as co-morbid diseases in clinical setting. In research it has been reported that one will influence the outcome of other disease. Hence, the psychiatrist should be aware of the interactions between immunomodulatory drugs and antipsychotics for better treatment outcomes.Aim:To understand clinically important drug-drug interaction and challenges in management of two middle aged females diagnosed with chronic rheumatoid arthritis and co-morbid schizophrenia.Result:We report 2 cases of RA with co morbid SCZ. The first case was maintaining on prednisolone and etanercept for RA and showed poor reponse to risperidone due to interaction with anti-rheumatoid drugs. The patient then improved on clozapine. The second case was being treated with methotrexate and olanzapine was initiated which showed improvement in schizophrenic as well as pain symptoms associated with RA.Conclusion:The metabolism of Risperidone can be increased when combined with Etanercept leading to reduced serum antipsychotic level and failure of treatment as found in this case. Also, olanzapine has unique pharmacological properties which can act as an adjunct to other pain medications prescribed for relief in RA patients. In the present cases, clozapine and olanzapine were beneficial respectively and therefore may be preferred over risperidone for management of schizophrenic patients with RA.

Effect of major components of Tripterygium wilfordii Hook. f on the uptake function of organic anion transporting polypeptide 1B1

Organic anion transporting polypeptide 1B1 (OATP1B1), which is specifically expressed at the basolateral membrane of human hepatocytes, is well recognized as the key determinant in the pharmacokinetics of a wide variety of drugs and considered as an important drug-drug interaction (DDI) site. Triptergium wilfordii Hook. f. (TWHF) is a traditional Chinese medicine that has a long history in treating diseases and more pharmacological effects were demonstrated recently. Components of TWHF mainly belong to the groups of alkaloids, diterpenoids, and triterpenoids. However, whether TWHF constituents are involved in herb-drug interaction (HDI) remains largely unknown. In the present study, we investigated the effect of four major components of TWHF, i.e. Triptolide (TPL), Celastrol (CL), and two alkaloids Wilforine (WFR) and Wilforgine (WFG) on the function of OATP1B1. It was found that co-incubation of these compounds greatly inhibited the uptake function of OATP1B1, with WFG (IC50 = 3.63 ± 0.61 μM) and WFR (IC50 = 3.91 ± 0.30 μM) showing higher inhibitory potency than TPL (IC50 = 184 ± 36 μM) and CL (IC50 = 448 ± 81 μM). Kinetic analysis revealed that co-incubation of WFG or WFR led to the reduction of both Km and Vmax of the DCF uptake. On the other hand, pre-incubation of WFG or WFR increased Km value of OATP1B1; while CL affected both Km and Vmax. In conclusion, co- and pre-incubation of the tested TWHF components inhibited OATP1B1 activity in different manners. Although co-incubation of WFG and WFR did not seem to directly compete with the substrates, pre-incubation of these alkaloids may alter the substrate-transporter interaction.