ArticleXenobiotica; the fate of foreign compounds in biological systems2008
Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination.
Article in Xenobiotica; the fate of foreign compounds in biological systems, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
58 citing papers in PubMed, 1 synthesis or guideline pooled it, 112 citations in OpenAlex.
- A systematic review of pregnancy-related clinical intervention of drug regimens due to pharmacokinetic reasons.Frontiers in medicine · 2023Pooled it
- Dolutegravir pharmacokinetics in pregnant and postpartum women living with HIV.AIDS (London, England) · 2018Trial
- Transdermal Estradiol Treatment for Postpartum Depression: A Pilot, Randomized Trial.Journal of clinical psychopharmacology · 2015Trial
- CYP2C19 genotype has a major influence on labetalol pharmacokinetics in healthy male Chinese subjects.European journal of clinical pharmacology · 2013Trial
- Influence of gestational diabetes mellitus on the stereoselective kinetic disposition and metabolism of labetalol in hypertensive patients.European journal of clinical pharmacology · 2011Trial
- Physiologically-based pharmacokinetic modelling of uridine 5'-diphosphoglucorosultransferase (UGT) substrate drugs in pregnant women.British journal of clinical pharmacology · 2026Article
- Microbiome-derived cancer: the catabolism of bilirubin to urobilin in the liver-gut axis and its consequences.Gastroenterology report · 2026Review
- Sex differences in hepatic enzymes and transporters involved in pharmacokinetics.Liver research (Beijing, China) · 2025Review
- Mechanisms of altered hepatic drug disposition during pregnancy: small molecules.Expert opinion on drug metabolism & toxicology · 2025Review
- Labetalol Dosing in Pregnancy: PBPK/PD and CYP2C19 Polymorphisms.Journal of clinical pharmacology · 2024Article
- Article
- Physiologically Based Pharmacokinetic Modeling for Multiple Oral Administration Labetalol in Pregnant Women.Pharmaceutical research · 2023Article
- Metabolic Profiling and Investigation of the Modulatory Effect ofAntioxidants (Basel, Switzerland) · 2023Article
- HIV-1 Integrase Strand Transfer Inhibitors and Neurodevelopment.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Impact of pregnancy related hormones on drug metabolizing enzyme and transport protein concentrations in human hepatocytes.Frontiers in pharmacology · 2022Article
- The Impact of Pregnancy on Antihypertensive Drug Metabolism and Pharmacokinetics: Current Status and Future Directions.Expert opinion on drug metabolism & toxicology · 2021Review
- Pregnancy-Related Hormones Increase UGT1A1-Mediated Labetalol Metabolism in Human Hepatocytes.Frontiers in pharmacology · 2021Article
- Pregnancy-Related Hormones Increase Nifedipine Metabolism in Human Hepatocytes by Inducing CYP3A4 Expression.Journal of pharmaceutical sciences · 2021Article
- Prediction of Maternal and Fetal Pharmacokinetics of Dolutegravir and Raltegravir Using Physiologically Based Pharmacokinetic Modeling.Clinical pharmacokinetics · 2020Article
- Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The authors recently reported the increased oral clearance of labetalol in pregnant women. To elucidate the mechanism of the elevated oral clearance, it was hypothesized that female hormones, at the high concentrations attainable during pregnancy, enhance hepatic metabolism of labetalol. Labetalol glucuronidation, which is the major elimination pathway of labetalol, was characterized by screening six recombinant human UGTs (UGT1A1, 1A4, 1A6, 1A9, 2B4, and 2B7) for their capacity to catalyse labetalol glucuronidation. The effect of female hormones (progesterone, oestradiol, oestriol, or oestrone) on the promoter activities of relevant UDP glucuronosyltransferases (UGT) was investigated using a luciferase reporter assay in HepG2 cells. The involvement of oestrogen receptor alpha (ERalpha) and pregnane X receptor (PXR) was examined by co-transfecting ERalpha- or PXR-constructs. UGT1A1 and UGT2B7 were identified as the major UGT enzymes producing labetalol glucuronides (trace amount of glucuronide conjugate was formed by UGT1A9). The activities of the UGT1A1 promoter containing PXR response elements were enhanced by progesterone, but not by oestrogens, indicating PXR-mediated induction of UGT1A1 promoter activity by progesterone. Results from semi-quantitative real-time polymerase chain reaction (PCR) assays are consistent with the above findings. This effect of progesterone on UGT1A1 promoter activities was concentration dependent. Promoter activities of UGT2B7 were not affected by either oestrogens or progesterone. The results suggest a potential role for progesterone in regulating labetalol elimination by modulating the expression of UGT1A1, leading to enhanced drug metabolism during pregnancy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.