UGT2B17 Genetic Polymorphisms Dramatically Affect the Pharmacokinetics of MK-7246 in Healthy Subjects in a First-in-Human Study

Wang, YH; Trucksis, Michele; Jj, McElwee; Ps, Wong; Maciolek, Cheri M; Thompson, Charles D.; Prueksaritanont, Thomayant; Gc, Garrett; Declercq, Ruben; Vets, Eva; Kj, Willson; Rc, Smith; Ja, Klappenbach; Opiteck, GJ; Ja, Tsou; Gibson, Christopher R; Laethem, Tine; Panorchan, Paul; Iwamoto, Marian; Pm, Shaw; Ja, Wagner; Jc, Harrelson

doi:10.1038/clpt.2012.20

Cited by 44 publications

(47 citation statements)

References 18 publications

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“…Nevertheless, case reports exist in the literature related to UGT1A1 (Meza-Junco et al, 2009;Riedmaier et al, 2010), UGT1A3 (Riedmaier et al, 2010), and UGT2B17 (Wang et al, 2012). In a recent report (Wang et al, 2012), UGT2B17 poor metabolizers had a mean exposure to This research was supported by F. Hoffmann-La Roche Ltd. M.F. is a coauthor on a patent application (no.…”

Section: Introductionmentioning

confidence: 99%

“…The likelihood of significant drug-drug interaction or polymorphic clearance due to UGT activity, which requires dose adjustment, is therefore often assumed to be low (Williams et al, 2004). Nevertheless, case reports exist in the literature related to UGT1A1 (Meza-Junco et al, 2009;Riedmaier et al, 2010), UGT1A3 (Riedmaier et al, 2010), and UGT2B17 (Wang et al, 2012). In a recent report (Wang et al, 2012), UGT2B17 poor metabolizers had a mean exposure to This research was supported by F. Hoffmann-La Roche Ltd. M.F.…”

Section: Introductionmentioning

confidence: 99%

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A UGT2B10 Splicing Polymorphism Common in African Populations May Greatly Increase Drug Exposure

Fowler

Kletzl

Finel

et al. 2014

J Pharmacol Exp Ther

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RO5263397 [(S)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine], a new compound that showed promising results in animal models of schizophrenia, is mainly metabolized in humans by N-glucuronidation. Enzyme studies, using the (then) available commercial uridine 59-diphosphate-glucuronosyltransferases (UGTs), suggested that UGT1A4 is responsible for its conjugation. In the first clinical trial, in which RO5263397 was administered orally to healthy human volunteers, a 136-fold above-average systemic exposure to the parent compound was found in one of the participants. Further administration in this trial identified two more such poor metabolizers, all three of African origin. Additional in vitro studies with recombinant UGTs showed that the contribution of UGT2B10 to RO5263397 glucuronidation is much higher than UGT1A4 at clinically relevant concentrations. DNA sequencing in all of these poor metabolizers identified a previously uncharacterized splice site mutation that prevents assembly of full-length UGT2B10 mRNA and thus functional UGT2B10 protein expression. Further DNA database analyses revealed the UGT2B10 splice site mutation to be highly frequent in individuals of African origin (45%), moderately frequent in Asians (8%) and almost unrepresented in Caucasians (,1%). A prospective study using hepatocytes from 20 individual African donors demonstrated a .100-fold lower intrinsic clearance of RO5263397 in cells homozygous for the splice site variant allele. Our results highlight the need to include UGT2B10 when screening the human UGTs for the enzymes involved in the glucuronidation of a new compound, particularly when there is a possibility of N-glucuronidation. Moreover, this study demonstrates the importance of considering different ethnicities during drug development.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A UGT2B10 Splicing Polymorphism Common in African Populations May Greatly Increase Drug Exposure

Fowler

Kletzl

Finel

et al. 2014

J Pharmacol Exp Ther

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“…UGT2B17 is of interest as it is highly polymorphic and copy number variations in its genes are associated with multiple potentially testosterone related pathologies (e.g., obesity,17 prostate cancer,18 osteoporosis,19 ankylosing spondylitis,20 and endometrial cancer) 21. UGT2B17 is highly expressed in the intestines and the liver 22, 23. Because of this and its known role in testosterone metabolism, we hypothesized that the first‐pass metabolism of testosterone by UGT2B17 is the main reason for its poor or variable bioavailability.…”

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confidence: 99%

Effect of Dose and 5α‐Reductase Inhibition on the Circulating Testosterone Metabolite Profile of Men Administered Oral Testosterone

Basit

Amory

Prasad

2018

Clinical Translational Sci

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Development of an oral testosterone therapy has proven extremely challenging because of extensive and variable first‐pass metabolism. We investigated the in vivo metabolism of testosterone with increasing oral doses of testosterone, both alone and with the co‐administration of dutasteride (5α‐reductase inhibitor) by liquid‐chromatography tandem mass spectrometry (LC‐MS/MS). In eugonadal men prior to dosing, the circulating concentration of testosterone, androstenedione, etiocholanolone‐glucuronide, and androsterone‐glucuronide was 8.6, 20.9, 9.1, and 55.3%, respectively, of the total testosterone‐related species, whereas testosterone‐glucuronide was ∼1%. When testosterone was dosed orally to men with experimental hypogonadism, a proportion of testosterone‐glucuronide increased to 13%. Dutasteride treatment significantly decreased levels of androsterone and its metabolites. This work reveals extensive metabolism of orally dosed testosterone to androsterone glucuronide via androstenedione, with testosterone‐glucuronide appearing to be the second most important metabolite. This information is of importance in the development of an effective oral testosterone therapy and may have implications for testosterone doping research.

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“…(Kang et al, 2010;Sadeque et al, 2012). Recently it was discovered that some individuals lack the UGT2B17 gene (Wilson et al, 2004) and that individuals homozygous for the deletion polymorphism excrete androgens and several drugs at a much lower rate compared with those expressing UGT2B17 (Jakobsson et al, 2006;Wong et al, 2011;Wang et al, 2012). The dual role in conjugation of androgens and therapeutic drugs opens the probability of drugendobiotic interaction with the potential risk of endocrine disruption or therapeutic failure.…”

Section: Introductionmentioning

confidence: 99%

Tissue Distribution and Relative Gene Expression of UDP-Glucuronosyltransferases (2B7, 2B15, 2B17) in the Human Fetus

2012

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UDP-glucuronosyltransferases (UGTs) catalyze phase II conjugation reactions and play an important role in the inactivation and elimination of several drugs. It is well known that the UGT activity in fetal livers is low compared with the UGT activity in adult livers. In this study the mRNA expression levels of the three human subfamilies, 2B7, 2B15, and 2B17, were determined in 20 adult and 60 fetal liver tissue specimens. The expression profile in fetal kidneys (N = 43), adrenals (N = 46), and lungs (N = 37) was also determined. All fetal and adult samples were genotyped for the UGT2B17 deletion polymorphism. Adult liver contained 13-36 times higher levels of UGT2B mRNAs as compared with fetal livers. UGT2B7 was most abundant in fetal lungs and kidneys, whereas UGT2B15 and UGT2B17 were predominant in the liver. There was a significant correlation between UGT2B7 expression levels in lungs and kidneys, whereas for the other UGT2Bs no correlation between the different tissues was observed. Fetuses expressing two UGT2B17 alleles (ins/ins) displayed significantly higher levels of UGT2B17 mRNA compared to ins/del fetuses in lungs, whereas in the other tissues no gene dose-effect was observed.

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UGT2B17 Genetic Polymorphisms Dramatically Affect the Pharmacokinetics of MK-7246 in Healthy Subjects in a First-in-Human Study

Cited by 44 publications

References 18 publications

A UGT2B10 Splicing Polymorphism Common in African Populations May Greatly Increase Drug Exposure

A UGT2B10 Splicing Polymorphism Common in African Populations May Greatly Increase Drug Exposure

Effect of Dose and 5α‐Reductase Inhibition on the Circulating Testosterone Metabolite Profile of Men Administered Oral Testosterone

Tissue Distribution and Relative Gene Expression of UDP-Glucuronosyltransferases (2B7, 2B15, 2B17) in the Human Fetus

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