Comments on “Shift from Biliary to Urinary Elimination of Acetaminophen-Glucuronide in Acetaminophen-Pretreated Rats”

Allegaert, Karel; Tibboel, Dick

doi:10.1124/jpet.105.096024

Cited by 5 publications

(5 citation statements)

References 6 publications

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“…Among MRP transporters, MRP3 may play a key role in sinusoidal efflux given reports citing its role in transporting acetaminophen glucuronide (Ghanem et al. ; Allegaert and Tibboel ) and morphine glucuronide (Zelcer et al. ) to the urine and blood stream.…”

Section: Discussionmentioning

confidence: 99%

“…Among MRP transporters, MRP3 may play a key role in sinusoidal efflux given reports citing its role in transporting acetaminophen glucuronide (Ghanem et al 2005;Allegaert and Tibboel 2006) and morphine glucuronide (Zelcer et al 2005) to the urine and blood stream. Furthermore, increases in Mrp3, in addition to UDP-glucuronosyltransferase (UGT) enzymes, have been reported in Mrp2-deficient rats (TR-rat; Johnson et al 2006).…”

Section: Discussionmentioning

confidence: 99%

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Species differences in sinusoidal and canalicular efflux transport of mycophenolic acid 7‐O‐glucuronide in sandwich‐cultured hepatocytes

Tetsuka

Gerst

Tamura

et al. 2014

Pharmacology Res & Perspec

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Metabolism and sinusoidal/canalicular efflux of mycophenolic acid (MPA) was investigated using sandwich-cultured hepatocytes (SCHs). After applying MPA to SCHs from humans, wild-type rats, and multidrug resistance-associated protein (Mrp) 2-deficient rats, the MPA metabolites 7-O-glucuronide (MPAG) and acyl glucuronide (AcMPAG) were detected in the intracellular compartment of the SCHs. Sinusoidal efflux of MPAG was detected in all SCH preparations including Mrp2-deficient rat SCHs, whereas canalicular efflux of MPAG was observed in wild-type rat and human SCHs but not in Mrp2-deficient rat SCHs. The ratio of canalicular efflux to net (canalicular plus sinusoidal) efflux was 37 ± 8% in wild-type rat SCHs, while the ratio in human SCHs was significantly lower (20 ± 2%, P < 0.05), indicating species differences in the direction of hepatic MPAG transport. This 20% ratio in human SCHs corresponds to a high sinusoidal MPAG efflux (80%) that can in part account for the urine-dominated recovery of MPAG in humans. Both sinusoidal and canalicular MPAG efflux in rat SCHs shows a good correspondence to urinary and biliary recovery of MPAG after MPA dosing. The sinusoidal efflux of AcMPAG in human SCHs was detected from one out of three donors, suggesting donor-to-donor variation. In conclusion, this study demonstrates the predictive value of SCHs for elucidating the interplay of metabolism and efflux transport, in addition to demonstrating a species difference between rat and human in sinusoidal and canalicular efflux of MPAG.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Species differences in sinusoidal and canalicular efflux transport of mycophenolic acid 7‐O‐glucuronide in sandwich‐cultured hepatocytes

Tetsuka

Gerst

Tamura

et al. 2014

Pharmacology Res & Perspec

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“…In our study, both the plasma and the urine AAP-glu/AAP-sul ratio were related to age; the plasma ratio increased from 0.32 in neonates to 1.23 in 6-year-old children with a similar increase in urine. The AAP-glu/AAP-sul ratio served as a surrogate marker for the relative contribution of glucuronidation and sulfation to AAP metabolism as in previous studies [ 18 , 19 , 21 , 37 ]. Previous studies reported changes in the urinary metabolites ratio after oral AAP administration from 0.27 in 2- to 3-day-old neonates, to 0.69 in 12-month-old infants, 0.81 in 2-year-old infants, 0.75 in 3- to 9-year-old children, 1.61 in 12-year-old children to 1.8 in adults [ 18 , 21 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Successful Use of [14C]Paracetamol Microdosing to Elucidate Developmental Changes in Drug Metabolism

Mooij

Duijn²,

Knibbe

et al. 2017

Clin Pharmacokinet

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BackgroundWe previously showed the practical and ethical feasibility of using [14C]-microdosing for pharmacokinetic studies in children. We now aimed to show that this approach can be used to elucidate developmental changes in drug metabolism, more specifically, glucuronidation and sulfation, using [14C]paracetamol (AAP).MethodsInfants admitted to the intensive care unit received a single oral [14C]AAP microdose while receiving intravenous therapeutic AAP every 6 h. [14C]AAP pharmacokinetic parameters were estimated. [14C]AAP and metabolites were measured with accelerator mass spectrometry. The plasma area under the concentration-time curve from time zero to infinity and urinary recovery ratios were related to age as surrogate markers of metabolism.ResultsFifty children [median age 6 months (range 3 days–6.9 years)] received a microdose (3.3 [2.0–3.5] ng/kg; 64 [41–71] Bq/kg). Plasma [14C]AAP apparent total clearance was 0.4 (0.1–2.6) L/h/kg, apparent volume of distribution was 1.7 (0.9–8.2) L/kg, and the half-life was 2.8 (1–7) h. With increasing age, plasma and urinary AAP-glu/AAP and AAP-glu/AAP-sul ratios significantly increased by four fold, while the AAP-sul/AAP ratio significantly decreased.ConclusionUsing [14C]labeled microdosing, the effect of age on orally administered AAP metabolism was successfully elucidated in both plasma and urine. With minimal burden and risk, microdosing is attractive to study developmental changes in drug disposition in children.

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“…18 We initially concluded that the increase in glucuronidation to overall paracetamol urinary elimination during repeated administration reflected induction of UGT activity. 30 Ghanem et al 31 however provided evidence in support of a shift from biliary to urinary elimination of paracetamol glucuronide (APAP-G) during repeated administration of paracetamol in rodents. This progressive increase in urinary elimination has recently been confirmed in healthy young adults to whom 4, 6, or 8 g of paracetamol was administered for 3 consecutive days.…”

Section: Compound-specific Observations On the In Vivo Phenotypic Glumentioning

confidence: 95%

In Vivo Glucuronidation Activity of Drugs in Neonates: Extensive Interindividual Variability Despite Their Young Age

Allegaert¹,

Vanhaesebrouck²,

Verbesselt³

et al. 2009

Therapeutic Drug Monitoring

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Compared with phase I isoenzymes, data on isoenzyme-specific phenotypic activity of uridine diphosphate glucuronosyltransferase (UGT) and its covariates in neonates are limited. In vivo observations on morphine, paracetamol (acetaminophen), and propofol disposition throughout childhood confirm the overall low-glucuronidation activity in neonates observed in in vitro studies. In addition to the phenotypic low-glucuronidation activity, in vivo observations of bilirubin (UGT1A1), morphine (UGT2B7), paracetamol (UGT1A6), and propofol (UGT1A9) glucuronidation in neonates display extensive interindividual variability, only in part explained by postmenstrual and postnatal age. Covariates like disease state characteristics (decreased morphine metabolism during therapeutic head cooling), genetic polymorphisms (UGT1A1 genetic variants and differences in bilirubin metabolism), or environmental factors (increased urinary excretion of paracetamol-glucuronide by repeated administration of paracetamol) further contribute to this variability. A focused approach to unveil covariates of the interindividual range is needed to improve our knowledge on drug disposition in early life.

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Comments on “Shift from Biliary to Urinary Elimination of Acetaminophen-Glucuronide in Acetaminophen-Pretreated Rats”

Cited by 5 publications

References 6 publications

Species differences in sinusoidal and canalicular efflux transport of mycophenolic acid 7‐O‐glucuronide in sandwich‐cultured hepatocytes

Species differences in sinusoidal and canalicular efflux transport of mycophenolic acid 7‐O‐glucuronide in sandwich‐cultured hepatocytes

Successful Use of [14C]Paracetamol Microdosing to Elucidate Developmental Changes in Drug Metabolism

In Vivo Glucuronidation Activity of Drugs in Neonates: Extensive Interindividual Variability Despite Their Young Age

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