The 1β-Hydroxy-Deoxycholic Acid to Deoxycholic Acid Urinary Metabolic Ratio: Toward a Phenotyping of CYP3A Using an Endogenous Marker?

In this study, we assessed the potential use of the 1β-hydroxy-deoxycholic acid (1β-OH-DCA) to deoxycholic acid (DCA) urinary metabolic ratio (UMR) as a CYP3A metric in ten male healthy volunteers. Midazolam (MDZ) 1 mg was administered orally at three sessions: alone (control session), after pre-treatment with fluvoxamine 50 mg (12 h and 2 h prior to MDZ administration), and voriconazole 400 mg (2 h before MDZ administration) (inhibition session), and after a 7-day pre-treatment with the inducer rifampicin 600 mg (induction session). The 1β-OH-DCA/DCA UMR was measured at each session, and correlations with MDZ metrics were established.

Impact of Acute Inflammation on Cytochromes P450 Activity Assessed by the Geneva Cocktail.

Cytochromes P450 (CYP) are subject to important interindividual variability in their activity due to genetic and environmental factors and some diseases. Limited human data support the idea that inflammation downregulates CYP activities. Our study aimed to evaluate the impact of orthopedic surgery (acute inflammation model) on the activity of six human CYP.

Reduced levels of biomarkers of exposure in smokers switching to the Carbon-Heated Tobacco Product 1.0: a controlled, randomized, open-label 5-day exposure trial.

In addition to smoking cessation, for those who would otherwise continue to smoke, replacing cigarettes with less harmful alternatives can reduce the harms of smoking. Heating instead of burning tobacco reduces, or eliminates, the formation of harmful and potentially harmful constituents (HPHC) that are found in cigarette smoke. The Carbon-Heated Tobacco Product (CHTP), a heat-not-burn tobacco product, mimics the cigarette smoking ritual.

Exposure to harmful and potentially harmful constituents decreased in smokers switching to Carbon-Heated Tobacco Product.

Background: "Heat-not-burn" tobacco products are designed to heat processed tobacco instead of combusting it, thus significantly reducing the formation of harmful and potentially harmful constituents (HPHCs) found in cigarette smoke, and ultimately reducing the risk of smoking-related diseases. The Carbon-Heated Tobacco Product (CHTP), a heat-not-burn tobacco product similar in appearance and use ritual to cigarettes, has been developed for smokers who would otherwise continue smoking as an alternative to cigarettes. To evaluate reduced risk of harm potential of CHTP, it is critical to quantify exposure to HPHCs and consequent biological pathway disturbances involved in disease onset in smokers who switch to CHTP.

Interaction between Fexofenadine and CYP Phenotyping Probe Drugs in Geneva Cocktail.

Drug metabolic enzymes and transporters are responsible for an important variability in drug disposition. The cocktail approach is a sound strategy for the simultaneous evaluation of several enzyme and transporter activities for a personalized dosage of medications. Recently, we have demonstrated the reliability of the Geneva cocktail, combining the use of dried blood spots (DBS) and reduced dose of phenotyping drugs for the evaluation of the activity of six cytochromes and P-glycoprotein (P-gp).

Effects of Switching to a Heat-Not-Burn Tobacco Product on Biologically Relevant Biomarkers to Assess a Candidate Modified Risk Tobacco Product: A Randomized Trial.

Background: Cigarette smoking increases the risk of chronic diseases; heating instead of burning tobacco can lower these risks, contributing to tobacco harm reduction. This study (with 984 adult American smokers) examined whether favorable changes occur in 8 co-primary endpoints (HDL-C, WBC, FEV%pred, COHb, Total NNAL, sICAM-1, 11-DTX-B2, 8-epi-PGF2α) indicative of biological and functional effects when cigarette smokers switch to the heat-not-burn Tobacco Heating System 2.2 (THS).

Evaluation of Biological and Functional Changes in Healthy Smokers Switching to the Tobacco Heating System 2.2 Versus Continued Tobacco Smoking: Protocol for a Randomized, Controlled, Multicenter Study.

Background: Tobacco harm reduction, substituting less harmful tobacco products for combustible cigarettes, is a complementary approach for smokers who would otherwise continue to smoke. The Philip Morris International (PMI) Tobacco Heating System (THS) 2.2 is a novel tobacco product with the potential to reduce the risk of harm in smokers compared to continued smoking of combustible cigarettes.

Phenotypic Assessment of Drug Metabolic Pathways and P-Glycoprotein in Patients Treated With Antidepressants in an Ambulatory Setting.

Objective: Drug-metabolizing enzymes (DMEs), such as cytochrome P450 (CYP) enzymes, and transporters have emerged as major determinants of variability in drug metabolism and response. This study investigated the association between CYP and P-glycoprotein activities and plasma antidepressant concentration in an outpatient clinical setting. Secondary outcomes were antidepressant efficacy and tolerance.

Evaluation of Mutual Drug-Drug Interaction within Geneva Cocktail for Cytochrome P450 Phenotyping using Innovative Dried Blood Sampling Method.

Cytochrome P450 (CYP) activity can be assessed using a 'cocktail' phenotyping approach. Recently, we have developed a cocktail (Geneva cocktail) which combines the use of low-dose probes with a low-invasiveness dried blood spots (DBS) sampling technique and a single analytical method for the phenotyping of six major CYP isoforms. We have previously demonstrated that modulation of CYP activity after pre-treatment with CYP inhibitors/inducer could be reliably predicted using Geneva cocktail.

Severe Vincristine-induced Neuropathic Pain in a CYP3A5 Nonexpressor With Reduced CYP3A4/5 Activity: Case Study.

Purpose: Peripheral neuropathy is a frequent vincristine-induced adverse effect. Vincristine is a substrate of P-glycoprotein and is metabolized by the cytochrome P-450 (CYP) 3A5 and 3A4 isoforms, with CYP3A5 contributing to 75% of the intrinsic clearance of vincristine. Alterations in the function of these proteins may lead to an increase in vincristine toxicity.

Simultaneous LC-MS/MS quantification of P-glycoprotein and cytochrome P450 probe substrates and their metabolites in DBS and plasma.

Background: An LC-MS/MS method has been developed for the simultaneous quantification of P-glycoprotein (P-gp) and cytochrome P450 (CYP) probe substrates and their Phase I metabolites in DBS and plasma. P-gp (fexofenadine) and CYP-specific substrates (caffeine for CYP1A2, bupropion for CYP2B6, flurbiprofen for CYP2C9, omeprazole for CYP2C19, dextromethorphan for CYP2D6 and midazolam for CYP3A4) and their metabolites were extracted from DBS (10 µl) using methanol. Analytes were separated on a reversed-phase LC column followed by SRM detection within a 6 min run time.

Real-time monitoring of exhaled drugs by mass spectrometry.

Future individualized patient treatment will need tools to monitor the dose and effects of administrated drugs. Mass spectrometry may become the method of choice to monitor drugs in real time by analyzing exhaled breath. This review describes the monitoring of exhaled drugs in real time by mass spectrometry.

Analgesics in patients with hepatic impairment: pharmacology and clinical implications.

The physiological changes that accompany hepatic impairment alter drug disposition. Porto-systemic shunting might decrease the first-pass metabolism of a drug and lead to increased oral bioavailability of highly extracted drugs. Distribution can also be altered as a result of impaired production of drug-binding proteins or changes in body composition.

Ritonavir inhibits the two main prasugrel bioactivation pathways in vitro: a potential drug-drug interaction in HIV patients.

Prasugrel is an antiplatelet prodrug used in patients with acute coronary syndrome. Prasugrel is mainly bioactivated by cytochromes P450 3A4/5 and CYP2B6. HIV patients are at risk of cardiovascular disease, and the protease inhibitor ritonavir is a potent inhibitor of these 2 CYPs.