PharmGKB summary: sertraline pathway, pharmacokinetics

Huddart, Rachel; Hicks, J. Kevin; Ramsey, Laura B.; Smith, D. Max; Babilonia, Margarita Bobonis; Altman, Russ B.; Klein, Teri E.

doi:10.1097/fpc.0000000000000392

Cited by 62 publications

(59 citation statements)

References 145 publications

(151 reference statements)

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“…We found an Sertraline dose presented as median and range (min-max) and measured and dose-adjusted sertraline and desmethylsertraline plasma concentrations presented as medians, interquartile ranges (Q1-Q3) and ranges (min-max) overrepresentation of lower concentrations, with only a few notably higher concentrations as reported in non-pregnant populations, adding to the varying results from studies in pregnant women [7,12,17,42]. This variability is probably due to genetic differences in drug metabolic capacity, mainly caused by the polymorphism of the CYP2C19-enzyme [22,26]. We also observe an up to 10-fold variation in the alteration ratios between pregnant and non-pregnant state, with the median ratio just below 1 ( Table 3).…”

Section: Discussionmentioning

confidence: 99%

“…The levels of both albumin and AAP decrease during pregnancy, potentially affecting the sertraline plasma concentrations [21]. Multiple Cytochrome P450 (CYP) enzymes in the liver metabolize sertraline to its main weakly active metabolite Ndesmethylsertraline [22]. The activity of these enzymes is genetically coded [23].…”

Section: Introductionmentioning

confidence: 99%

“…Current consensus is that CYP2C19 has a major role in sertraline metabolism and that the genetic differences in its expression cause interindividual variability in sertraline concentrations. The importance of CYP2B6, CYP3A4, CYP2C9, and CYP2D6 for the disposition of sertraline in vivo is not yet clear [22,[24][25][26]. Pregnancy induces changes in metabolic enzyme activity, with the activity of CYP2C19 being slightly down-regulated, and the activities of the other potentially important enzymes being upregulated [7][8][9]21].…”

Section: Introductionmentioning

confidence: 99%

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Sertraline concentrations in pregnant women are steady and the drug transfer to their infants is low

Heinonen

Blennow

Blomdahl-Wetterholm

et al. 2021

Eur J Clin Pharmacol

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Purpose Sertraline, a selective serotonin reuptake inhibitor (SSRI), is one of the most commonly used antidepressant during pregnancy. Plasma sertraline concentrations vary markedly between individuals, partly explained by variability in hepatic drug metabolizing cytochrome P450-enzyme activity. Our purpose was to study the variability in the plasma concentrations in pregnant women and the passage to their infants. Method Pregnant women with moderate untreated depression were recruited in 2016–2019 in Stockholm Region and randomized to treatment with sertraline or placebo. All received Internet-based cognitive behavior therapy as non-medical treatment. Sertraline plasma concentrations were measured around pregnancy weeks 21 and 30, at delivery, 1-month postpartum, in cord blood and at 48 h of age in the infant. The clinical course of the infants was followed. Results Nine mothers and 7 infants were included in the analysis. Median dose-adjusted sertraline concentration in second trimester was 0.15(ng/mL) /(mg/day), in third trimester and at delivery 0.19 and 1-month postpartum 0.25, with a 67% relative difference between second trimester and postpartum. The interindividual variation was 10-fold. Median concentrations in the infants were 33% and 25% of their mothers’, measured in cord blood, and infant plasma, respectively. Only mild and transient adverse effects were seen on the infants. Conclusion Placental passage of sertraline to the infant is low. However, the interindividual variation in maternal concentrations during pregnancy is huge, why therapeutic drug monitoring might assist in finding the poor metabolizers at risk for adversity and increase the safety of the treatment. Trial registration The trial was registered at clinicaltrials.gov July 9, 2014 with TRN: NCT02185547.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sertraline concentrations in pregnant women are steady and the drug transfer to their infants is low

Heinonen

Blennow

Blomdahl-Wetterholm

et al. 2021

Eur J Clin Pharmacol

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“…For example, cilazapril, a 1,2‐diazepine derivative, is an angiotensin‐converting enzyme inhibitor used for the treatment of hypertension and congestive heart failure 15 ; 1,2‐diazepines (strictly benzo‐2,3‐diazepines), that is, tofispam, nérisopam, girisopam, showed potent anxiolytic and antipsychotic properties or are used in the treatment of epilepsy (talampanel) 16 . Regarding 1,5‐diazepines, only one compound is currently in the market: clobazam, 17 which is an antiepileptic, anxiolytic, hypnotic, and myorelaxant compound, while other derivatives are in clinic trials such as diazepinomycin currently evaluated for the treatment of glioblastoma 18 . Concerning the 1,3‐diazepine scaffold it is present in numerous biological active compounds, including natural products (see below), and was used to prepare compounds displaying a large range of biological activities.…”

Section: Introductionmentioning

confidence: 99%

1,3‐Diazepine: A privileged scaffold in medicinal chemistry

Malki

Martinez

Masurier

2021

Medicinal Research Reviews

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Privileged structures have been widely used as effective templates for drug discovery. While benzo‐1,4‐diazepine constitutes the first historical example of such a structure, the 1,3 analogue is just as rich in terms of applications in medicinal chemistry. The 1,3‐diazepine moiety is present in numerous biological active compounds including natural products, and is used to design compounds displaying a large range of biological activities. It is present in the clinically used anticancer compound pentostatin, in several recent FDA approved β‐lactamase inhibitors (e.g., avibactam) and also in coformycin, a natural product known as a ring‐expanded purine analogue displaying antiviral and anticancer activities. Several other 1,3‐diazepine containing compounds have entered into clinical trials. This heterocyclic structure has been and is still widely used in medicinal chemistry to design enzyme inhibitors, GPCR ligands, and so forth. This review endeavours to highlight the main use of the 1,3‐diazepine scaffold and its derivatives, and their applications in medicinal chemistry, drug design, and therapy. We will focus more particularly on the development of enzyme inhibitors incorporating this scaffold, with a strong emphasis on the molecular interactions involved in the inhibition mechanism.

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“…Another part is excreted after glucuronidation by UGT2B7. Both oxymorphone and nor-oxycodone are subsequently metabolized into nor-oxymorphone ( Figure 1 ) [ 4 , 7 ]. All metabolites have an affinity for the μ-opioid receptor; however, the exact contribution of each metabolite to the analgesic effect is unknown [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetics of Oxycodone and Metabolites in Patients with Cancer-Related Pain

Agema

Oosten

Sassen

et al. 2021

Cancers

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Oxycodone is frequently used for treating cancer-related pain, while not much is known about the factors that influence treatment outcomes in these patients. We aim to unravel these factors by developing a population-pharmacokinetic model to assess the pharmacokinetics of oxycodone and its metabolites in cancer patients, and to associate this with pain scores, and adverse events. Hospitalized patients with cancer-related pain, who were treated with oral oxycodone, could participate. Pharmacokinetic samples and patient-reported pain scores and occurrence and severity of nine adverse events were taken every 12 h. In 28 patients, 302 pharmacokinetic samples were collected. A one-compartment model for oxycodone and each metabolite best described oxycodone, nor-oxycodone, and nor-oxymorphone pharmacokinetics. Furthermore, oxycodone exposure was not associated with average and maximal pain scores, and oxycodone, nor-oxycodone, and nor-oxymorphone exposure were not associated with adverse events (all p > 0.05). This is the first model to describe the pharmacokinetics of oxycodone including the metabolites nor-oxycodone and nor-oxymorphone in hospitalized patients with cancer pain. Additional research, including more patients and a more timely collection of pharmacodynamic data, is needed to further elucidate oxycodone (metabolite) pharmacokinetic/pharmacodynamic relationships. This model is an important starting point for further studies to optimize oxycodone dosing regiments in patients with cancer-related pain.

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PharmGKB summary: sertraline pathway, pharmacokinetics

Cited by 62 publications

References 145 publications

Sertraline concentrations in pregnant women are steady and the drug transfer to their infants is low

Sertraline concentrations in pregnant women are steady and the drug transfer to their infants is low

1,3‐Diazepine: A privileged scaffold in medicinal chemistry

Population Pharmacokinetics of Oxycodone and Metabolites in Patients with Cancer-Related Pain

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