Induction Of Hepatic Cytochrome P450 Enzymes Research Articles

Coadministration of Voriconazole and Rifabutin Can Increase the Risk of Adverse Drug Reactions in Patients with Multiple Infections.

Coinfection of tuberculosis or nontuberculous mycobacteria and Aspergillus presents a challenge in medication selection because of the pharmacokinetic interactions between rifampin and voriconazole. Some researchers have suggested the use of rifabutin as an alternative to rifampin because of its lower hepatic cytochrome P450 enzyme induction potency despite its contraindication to drug labels. This study presents clinical cases of voriconazole and rifabutin coadministration and their potential risks. This retrospective study was conducted using clinical data from patients who met the following criteria: (1) admitted to Seoul National University Hospital between July 2014 and August 2023 and (2) concurrently administered rifabutin and voriconazole for more than 5 days. Among the 6 patients analyzed, 4 experienced adverse drug reactions (ADRs). Three patients experienced visual and auditory hallucinations, lower extremity numbness, or delirious behavior. Two patients had prolonged the time from the start of the Q wave to the end of the T wave intervals, and 1 had elevated aspartate aminotransferase and alanine aminotransferase levels. In addition, 2 patients experienced severe nausea, poor oral intake, and weight loss. Despite receiving 1.81-fold the recommended voriconazole dosage, a therapeutic concentration (1.0-5.5 mg/L) was not achieved because of cytochrome P450 induction by rifabutin. However, during septic shock, the voriconazole concentration increased by 13.7- to 36-fold. Concurrent use of rifabutin and voriconazole was associated with ADRs, including the time from the start of the Q wave to the end of the T wave prolongation, hallucinations, and severe nausea. Moreover, initially, there was a significant decrease in voriconazole concentrations; however, these concentrations substantially increased during septic shock. Therefore, it is essential to monitor drug concentrations and ADRs during concurrent use of voriconazole and rifabutin.

Computational pharmacology of rifampin in mice: an application to dose optimization with conflicting objectives in tuberculosis treatment.

Dose selection for rifampin in the treatment of active pulmonary tuberculosis (TB) illustrates some of the challenges for dose optimization within multidrug therapies. Rifampin-based anti-TB regimens are often combined with antiretroviral therapies to treat human immunodeficiency virus (HIV) coinfection. The potent cytochrome P450 (CYP) enzyme inducing properties of rifampin give rise to significant drug-drug interactions, the minimization of which by limiting the dose, conflicts with the maximization of bacterial killing by increasing the dose. Such multiple and conflicting objectives lead to a set of trade-off optimal solutions for dose optimization rather than a single best solution. Here, we combine pharmacokinetic/pharmacodynamic (PK/PD) modeling with multiobjective optimization to quantitatively explore trade-offs between therapeutic and adverse effects of optimal dosing for the example of rifampin in TB-infected mice. The PK/PD model describes rifampin concentrations in plasma and liver following oral administration together with hepatic CYP enzyme induction and bacterial killing kinetics. We include optimization objectives descriptive of antimicrobial efficacy, CYP-mediated drug-drug interactions, and drug exposure-dependent toxicity. Results show non-conventional dosing scenarios that allow for increased efficacy relative to uniform dosing without increasing drug-drug interactions. Additionally, we find currently employed dosages for rifampin to be nearly optimal with respect to trade-offs between efficacy and toxicity. While limited by the accuracy and applicability of the PK/PD model, these results provide an avenue for experimental investigation of complex dose optimization problems. This method can be extended to include additional drugs and optimization objectives, and may provide a useful tool for individualized medicine.

Alteration in Metabolism and Toxicity of Acetaminophen Upon Repeated Administration in Rats

Our previous studies showed that administration of a subtoxic dose of acetaminophen (APAP) to female rats increased generation of carbon monoxide from dichloromethane, a metabolic reaction catalyzed mainly by cytochrome P450 (CYP) 2E1. In this study we examined the changes in metabolism and toxicity of APAP upon repeated administration. An intraperitoneal dose of APAP (500 mg/kg) alone did not increase aspartate aminotransferase, alanine aminotransferase, or sorbitol dehydrogenase activity in serum, but was significantly hepatotoxic when the rats had been pretreated with an identical dose of APAP 18 h earlier. The concentrations and disappearance of APAP and its metabolites in plasma were monitored for 8 h after the treatment. APAP pretreatment reduced the elevation of APAP-sulfate, but increased APAP-cysteine concentrations in plasma. APAP or APAP-glucuronide concentrations were not altered. Administration of a single dose of APAP 18 h before sacrifice increased microsomal CYP activities measured with p-nitrophenol, p-nitroanisole, and aminopyrine as probes. Expression of CYP2E1, CYP3A, and CYP1A proteins in the liver was also elevated significantly. The results suggest that administration of APAP at a subtoxic dose may result in an induction of hepatic CYP enzymes, thereby altering metabolism and toxicological consequences of various chemical substances that are substrates for the same enzyme system.

Peripheral metabolism of (R)-[11C]verapamil in epilepsy patients

(R)-[(11)C]verapamil is a new PET tracer for P-glycoprotein-mediated transport at the blood-brain barrier. For kinetic analysis of (R)-[(11)C]verapamil PET data the measurement of a metabolite-corrected arterial input function is required. The aim of this study was to assess peripheral (R)-[(11)C]verapamil metabolism in patients with temporal lobe epilepsy and compare these data with previously reported data from healthy volunteers. Arterial blood samples were collected from eight patients undergoing (R)-[(11)C]verapamil PET and selected samples were analysed for radiolabelled metabolites of (R)-[(11)C]verapamil by using an assay that measures polar N-demethylation metabolites by solid-phase extraction and lipophilic N-dealkylation metabolites by HPLC. Peripheral metabolism of (R)-[(11)C]verapamil was significantly faster in patients compared to healthy volunteers (AUC of (R)-[(11)C]verapamil fraction in plasma: 29.4 +/- 3.9 min for patients versus 40.8 +/- 5.0 min for healthy volunteers; p < 0.0005, Student's t-test), which resulted in lower (R)-[(11)C]verapamil plasma concentrations (AUC of (R)-[(11)C]verapamil concentration, normalised to injected dose per body weight: 25.5 +/- 2.1 min for patients and 30.5 +/- 5.9 min for healthy volunteers; p = 0.038). Faster metabolism appeared to be mainly due to increased N-demethylation as the polar [(11)C]metabolite fraction was up to two-fold greater in patients. Faster metabolism of (R)-[(11)C]verapamil in epilepsy patients may be caused by hepatic cytochrome P450 enzyme induction by antiepileptic drugs. Based on these data caution is warranted when using an averaged arterial input function derived from healthy volunteers for the analysis of patient data. Moreover, our data illustrate how antiepileptic drugs may decrease serum levels of concomitant medication, which may eventually lead to a loss of therapeutic efficacy.

Investigation of hepatic cytochrome P-450 enzyme induction and DNA adduct formation in male CD/1 mice following oral administration of toxaphene

Investigation of hepatic cytochrome P-450 enzyme induction and DNA adduct formation in male CD/1 mice following oral administration of toxaphene

Investigation of hepatic cytochrome P-450 enzyme induction and DNA adduct formation in male CD/1 mice following oral administration of toxaphene

Exposure of experimental animals to toxaphene induces hepatic cytochrome P-450 (CYP). Although chronic administration of toxaphene to mice was found to cause an increased incidence of liver tumors, a mechanism for its carcinogenicity has yet to be elucidated. We investigated two potential mechanisms of toxaphene-induced carcinogenicity: peroxisomal proliferation and DNA binding. Peroxisomal proliferation was evaluated by measuring the level of immunodetectable CYP 4A1, an isozyme of CYP that is specifically induced by peroxisomal proliferators, in hepatic microsomes from CD1 mice that were treated by oral gavage for seven consecutive days with corn oil vehicle or 10, 25, 50 or 100 mg kg(-1) toxaphene. In comparison to control mice, toxaphene-treated mice had increased liver weight, increased liver/body weight ratios and increased levels of total hepatic CYP and cytochrome b5. No increase in the level of immunodetectable levels of CYP 4A1 was found in hepatic microsomes from toxaphene-treated mice when compared to controls. In contrast, increases in immunodetectable CYP 4A1 were detected in hepatic microsomes from mice treated with the peroxisomal proliferator clofibrate. These findings suggest that toxaphene-induced induction of CYP may not involve CYP 4A1 and that peroxisomal proliferation may not be involved in toxicity. Significant increases in immunodetectable levels of CYP 2B were, however, detected in toxaphene-treated mice, and are consistent with earlier reports demonstrating that toxaphene, like many other pesticides, induces the phenobarbital-inducible subfamily of CYP. Analysis of DNA adduct levels in the livers of toxaphene-treated mice by DNA 32P-post-labeling showed no evidence of DNA adduct formation.