| 1. |
- Allmyr, Mats, et al.
(author)
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Human Exposure to Triclosan via Toothpaste does not change CYP3A4 Activity or Plasma Concentrations of Thyroid Hormones
- 2009
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 105:5, s. 339-344
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Journal article (peer-reviewed)abstract
- Triclosan is an antibacterial compound commonly used in cosmetics and personal care products for everyday use. As previously shown, triclosan is found in the plasma, urine and milk from large parts of different human populations. Recent studies have revealed that triclosan is able to activate the human pregnane X receptor in vitro and thus possibly affecting metabolism of drugs in humans via the induction of CYP3A4. Besides, triclosan has been shown to affect thyroid hormonal levels in rats in vivo. In the present study, we investigated if an everyday exposure to triclosan via triclosan-containing toothpaste for 14 days in 12 adult humans caused an increase in plasma 4 beta-hydroxycholesterol, indicative of CYP3A4 induction, and/or alterations in thyroid hormonal status. The plasma triclosan concentrations increased from 0.009-0.81 ng/g to 26-296 ng/g (ranges) upon exposure. Despite this, there were no significant changes in plasma levels of either plasma 4 beta-hydroxycholesterol or thyroid hormones during the exposure. This indicates that the normal use of triclosan-containing toothpaste is not likely to alter metabolism of drugs via CYP3A4 induction or cause adverse events because of thyroid disturbances in humans.
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| 2. |
- Sparve, Erik
(author)
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Clinical studies of CYP3A4 and P-glycoprotein
- 2016
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Licentiate thesis (other academic/artistic)abstract
- In the field of pharmacokinetics, cytochrome P450 enzymes have been extensively studied. The CYP450 enzyme with the most drug substrates is CYP3A4, but despite its significance, administration of a specific substrate to subjects is required to determine its activity, by measuring the metabolic ratio. For reasons of feasibility and safety it would be preferable to have an endogenous biomarker instead of a probe drug. The activity of CYP3A4 varies considerably as it can be induced and inhibited by certain compounds. For example, it is induced by ligands to the Pregnane X receptor (PxR). Activation of this receptor also induces the drug transporter P-glycoprotein. Regarding genetic variability, it is well known that CYP3A4 does not display genetic polymorphism in activity, but results from studies of P-gp in that aspect have been inconclusive. In the first study of this thesis, which was also aiming to evaluate the inductive property of rifampicin on four other CYP450 enzymes, a probe drug and an endogenous biomarker were compared regarding their properties for measuring CYP3A4 activity. Induction was achieved by administration of rifampicin in three different doses (20-500 mg once daily) to healthy volunteers. The endogenous biomarker 4β-hydroxycholesterol had a linear relationship with the metabolic ratio of the CYP3A4 probe drug quinine. In this study four other probe drugs were also used simultaneously, each specific for a different CYP450 enzyme. All enzymes except CYP2D6 were induced by rifampicin. This cocktail had been designed not to cause any drug-drug interactions among the probes, which are also specific for each enzyme. In the second study, 4β-hydroxycholesterol was used to investigate whether exposure to triclosan in the doses reached by normal use of toothpaste can induce the enzyme. Triclosan activates PxR in vitro, but the results from our clinical study indicate that this effect is not relevant when subjects are exposed in the dose range achieved by normal use of toothpaste. In the third clinical study two common haplotypes of MDR1, which encode P-gp, were compared by phenotyping with the substrate digoxin. The haplotypes were chosen because they are common and because their clinical relevance has been under discussion for many years. Digoxin is the most commonly used drug for investigating P-gp activity as it is not metabolized and because it is a known substrate of this transporter. The difference in plasma digoxin kinetics was not statistically significant in our study and the study does not support that genetic variability in MDR1 has an impact on P-gp activity in the haplotypes investigated. Ligands to PxR also induce the drug transporter P-glycoprotein, which has largely overlapping substrate specificity with CYP3A4. Drug transporters have been considerably less studied than CYP450 enzymes but the knowledge is rapidly increasing and the focus has been mainly on P-gp because of its broad specificity. Even though CYP3A4 does not have polymorphic activity, it is well known that some CYP450 enzymes do, and the data on whether P-gp has such variability has been inconclusive.
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| 3. |
- Sparve, Erik, et al.
(author)
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Prediction and Modeling of Effects on the QTc Interval for Clinical Safety Margin Assessment, Based on Single-Ascending-Dose Study Data with AZD3839
- 2014
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In: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0022-3565 .- 1521-0103. ; 350:2, s. 469-478
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Journal article (peer-reviewed)abstract
- Corrected QT interval (QTc) prolongation in humans is usually predictable based on results from preclinical findings. This study confirms the signal from preclinical cardiac repolarization models (human ether-a-go-go-related gene, guinea pig monophasic action potential, and dog telemetry) on the clinical effects on the QTc interval. A thorough QT/QTc study is generally required for bioavailable pharmaceutical compounds to determine whether or not a drug shows a QTc effect above a threshold of regulatory interest. However, as demonstrated in this AZD3839 [(S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate] single-ascending-dose (SAD) study, high-resolution digital electrocardiogram data, in combination with adequate efficacy biomarker and pharmacokinetic data and nonlinear mixed effects modeling, can provide the basis to safely explore the margins to allow for robust modeling of clinical effect versus the electrophysiological risk marker. We also conclude that a carefully conducted SAD study may provide reliable data for effective early strategic decision making ahead of the thorough QT/QTc study.
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