Prediction of Hepatic Transporter-Mediated Drug–Drug Interaction from In Vitro Data

Background: Many antibiotics have a high potential for having an interaction with drugs, as perpetrator and/or victim, in critically ill patients, and particularly in sepsis patients. Methods: The aim of this review is to summarize the pharmacokinetic drug-drug interaction (DDI) of 45 antibiotics commonly used in sepsis care in China. Literature mining was conducted to obtain human pharmacokinetics/dispositions of the antibiotics, their interactions with drug metabolizing enzymes or transporters, and their associated clinical drug interactions. Potential DDI is indicated by a DDI index > 0.1 for inhibition or a treated-cell/untreated-cell ratio of enzyme activity being > 2 for induction. Results: The literature-mined information on human pharmacokinetics of the identified antibiotics and their potential drug interactions is summarized. Conclusion: Antibiotic-perpetrated drug interactions, involving P450 enzyme inhibition, have been reported for four lipophilic antibacterials (ciprofloxacin, erythromycin, trimethoprim, and trimethoprim-sulfamethoxazole) and three lipophilic antifungals (fluconazole, itraconazole, and voriconazole). In addition, seven hydrophilic antibacterials (ceftriaxone, cefamandole, piperacillin, penicillin G, amikacin, metronidazole, and linezolid) inhibit drug transporters in vitro. Despite no reported clinical PK drug interactions with the transporters, caution is advised in the use of these antibacterials. Eight hydrophilic antibacterials (all β-lactams; meropenem, cefotaxime, cefazolin, piperacillin, ticarcillin, penicillin G, ampicillin, and flucloxacillin), are potential victims of drug interactions due to transporter inhibition. Rifampin is reported to perpetrate drug interactions by inducing CYP3A or inhibiting OATP1B; it is also reported to be a victim of drug interactions, due to the dual inhibition of CYP3A4 and OATP1B by indinavir. In addition, three antifungals (caspofungin, itraconazole, and voriconazole) are reported to be victims of drug interactions because of P450 enzyme induction. Reports for other antibiotics acting as victims in drug interactions are scarce.

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Use of Toxicokinetics in Risk Assessment Based on In Vitro Data

Alternatives to Laboratory Animals ◽

10.1177/026119299302100209 ◽

1993 ◽

Vol 21 (2) ◽

pp. 173-180

Author(s):

Gunnar Johanson

Keyword(s):

Risk Assessment ◽

Whole Body ◽

External Exposure ◽

Target Dose ◽

Toxic Response ◽

Route Of Exposure ◽

Vitro Data ◽

In Vitro Data

This presentation addresses some aspects of the methodology, advantages and problems associated with toxicokinetic modelling based on in vitro data. By using toxicokinetic models, particularly physiologically-based ones, it is possible, in principle, to describe whole body toxicokinetics, target doses and toxic effects from in vitro data. Modelling can be divided into three major steps: 1) to relate external exposure (applied dose) of xenobiotic to target dose; 2) to establish the relationship between target dose and effect (in vitro data, e.g. metabolism in microsomes, partitioning in tissue homogenates, and toxicity in cell cultures, are useful in both steps); and 3) to relate external exposure to toxic effect by combining the first two steps. Extrapolations from in vitro to in vivo, between animal and man, and between high and low doses, can easily be carried out by toxicokinetic simulations. In addition, several factors that may affect the toxic response by changing the target dose, such as route of exposure and physical activity, can be studied. New insights concerning the processes involved in toxicity often emerge during the design, refinement and validation of the model. The modelling approach is illustrated by two examples: 1) the carcinogenicity of 1,3-butadiene; and 2) the haematotoxicity of 2-butoxyethanol. Toxicokinetic modelling is an important tool in toxicological risk assessment based on in vitro data. Many factors, some of which can, and should be, studied in vitro, are involved in the expression of toxicity. Successful modelling depends on the identification and quantification of these factors.

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Lymphocutaneous spread of Mycobacterium elephantis in an immunocompetent individual: A case report

SAGE Open Medical Case Reports ◽

10.1177/2050313x211034913 ◽

2021 ◽

Vol 9 ◽

pp. 2050313X2110349

Author(s):

Brett D Edwards ◽

Ranjani Somayaji ◽

Dina Fisher ◽

Justin C Chia

Keyword(s):

Case Report ◽

Chronic Lung Disease ◽

Contaminated Soil ◽

Lung Abscess ◽

Immunocompetent Individual ◽

First Case ◽

Antimycobacterial Agents ◽

Vitro Data ◽

In Vitro Data

Mycobacterium elephantis was first described when isolated from an elephant that succumbed to lung abscess. However, despite this namesake, it is not associated with animals and has been described most often as a probable colonizer rather than pathogen in humans with chronic lung disease. In this report, we describe the first case of lymphocutaneous infection from M. elephantis, likely as a result of cutaneous inoculation with contaminated soil. This offers further evidence to its capabilities as a pathogen. We provide a review of the limited prior reports of M. elephantis and outline the available in vitro data on efficacy of various antimycobacterial agents.

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Prediction of CYP2D6 Drug Interactions from In Vitro Data: Evidence for Substrate-Dependent Inhibition

Drug Metabolism and Disposition ◽

10.1124/dmd.111.041210 ◽

2011 ◽

Vol 40 (1) ◽

pp. 47-53 ◽

Cited By ~ 43

Author(s):

Brooke M. VandenBrink ◽

Robert S. Foti ◽

Dan A. Rock ◽

Larry C. Wienkers ◽

Jan L. Wahlstrom

Keyword(s):

Drug Interactions ◽

Dependent Inhibition ◽

Vitro Data ◽

In Vitro Data

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