Considering Age Variation When Coining Drugs as High versus Low Hepatic Extraction Ratio

Salem, Farzaneh; Abduljalil, Khaled; Kamiyama, Yoshiteru; Rostami‐Hodjegan, Amin

doi:10.1124/dmd.115.067595

Cited by 32 publications

(39 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Due to the lower intrinsic hepatic clearance, the hepatic extraction ratio is very low in preterm neonates compared with adults, resulting in a much higher hepatic bioavailability than expected based on adult values. This has been previously reported by Salem et al . who found that the hepatic extraction ratio of midazolam increased with age.…”

Section: Discussionsupporting

confidence: 85%

“…who found that the hepatic extraction ratio of midazolam increased with age. They found that the ontogeny of hepatic enzyme abundance and to a lesser extent the smaller number of microsomal protein per gram of liver contributed to the observed differences between preterm neonates and adults . Based on the hepatic intrinsic clearance, the hepatic blood flow, the fraction unbound in blood, and the blood:plasma ratio, the total plasma clearance can be calculated (Eq.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

First‐Pass CYP3A‐Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates

Brussee

Krekels

et al. 2018

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

To predict first‐pass and systemic cytochrome P450 (CYP) 3A‐mediated metabolism of midazolam in preterm neonates, a physiological population pharmacokinetic model was developed describing intestinal and hepatic midazolam clearance in preterm infants. On the basis of midazolam and 1‐OH‐midazolam concentrations from 37 preterm neonates (gestational age 26–34 weeks) receiving midazolam orally and/or via a 30‐minute intravenous infusion, intrinsic clearance in the gut wall and liver were found to be very low, with lower values in the gut wall (0.0196 and 6.7 L/h, respectively). This results in a highly variable and high total oral bioavailability of 92.1% (range, 67–95%) in preterm neonates, whereas this is around 30% in adults. This approach in which intestinal and hepatic clearance were separately estimated shows that the high bioavailability in preterm neonates is explained by, likely age‐related, low CYP3A activity in the liver and even lower CYP3A activity in the gut wall.

show abstract

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

First‐Pass CYP3A‐Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates

Brussee

Krekels

et al. 2018

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

show abstract

“…This could be due to the developmental increase in OCT1 and UGT2B7 protein expression and hepatic blood flow in the Simcyp Simulator. Similar to this finding, it was reported that the hepatic extraction ratio of midazolam, a CYP3A probe substrate, varies with age due to age‐dependent physiological changes, including hepatic CYP3A4 protein expression . From these findings, the hepatic extraction ratio in children, especially for high extraction drugs, can be different from that in adults due to the developmental change in physiological factors over age.…”

Section: Discussionsupporting

confidence: 81%

PBPK Model of Morphine Incorporating Developmental Changes in Hepatic OCT1 and UGT2B7 Proteins to Explain the Variability in Clearances in Neonates and Small Infants

Emoto

Johnson

Neuhoff

et al. 2018

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

Morphine has large pharmacokinetic variability, which is further complicated by developmental changes in neonates and small infants. The impacts of organic cation transporter 1 (OCT1) genotype and changes in blood‐flow on morphine clearance (CL) were previously demonstrated in children, whereas changes in UDP‐glucuronosyltransferase 2B7 (UGT2B7) activity showed a small effect. This study, targeting neonates and small infants, was designed to assess the influence of developmental changes in OCT1 and UGT2B7 protein expression and modified blood‐flow on morphine CL using physiologically based pharmacokinetic (PBPK) modeling. The implementation of these three age‐dependent factors into the pediatric system platform resulted in reasonable prediction for an age‐dependent increase in morphine CL in these populations. Sensitivity of morphine CL to changes in cardiac output increased with age up to 3 years, whereas sensitivity to changes in UGT2B7 activity decreased. This study suggests that morphine exhibits age‐dependent extraction, likely due to the developmental increase in OCT1 and UGT2B7 protein expression/activity and hepatic blood‐flow.

show abstract

“…47 Therefore, phenotypic and genotypic changes in CYP activity may partially explain the observed large PK variability of methadone in neonates and adults, which could be due to the low hepatic extraction ratio of methadone as observed in adults (ie, capacity-limited clearance). 48 In addition, AGP has been shown to increase during gestation and reach adult levels by 1 year of age. 35 These changes in protein binding could also contribute to methadone variability in neonates.…”

Section: Discussionmentioning

confidence: 99%

Utilizing Pediatric Physiologically Based Pharmacokinetic Models to Examine Factors That Contribute to Methadone Pharmacokinetic Variability in Neonatal Abstinence Syndrome Patients

McPhail

Emoto

Fukuda

et al. 2019

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Chronic intrauterine exposure to psychoactive drugs often results in neonatal abstinence syndrome (NAS). NAS is the symptomatic drug withdrawal in newborns that generally occurs after in utero chronic opioid exposure. Methadone is an opioid analgesic commonly prescribed for pharmacologic management of NAS. It exhibits high pharmacokinetic (PK) variability. The current study used physiologically based PK modeling to predict the PK profile of methadone in 20 newborns treated for NAS. The physiologically based PK simulations adequately predicted the PK profile of the clinical data for 45% of the patients. Sensitivity analyses were conducted to explore contributing factors to methadone PK variability. The data suggest that P450 enzymatic activity impacts the clearance of methadone in virtual adults and neonates, while the contribution of cardiac output may be negligible. Understanding maturational and/or pharmacogenetic changes in cytochrome P450 enzymatic activity may further explain the large PK variability of methadone in newborns with NAS and will help individualized treatment.

show abstract

Considering Age Variation When Coining Drugs as High versus Low Hepatic Extraction Ratio

Abstract: The hepatic extraction ratio (E H ) is commonly considered an "inherent attribute" of drug. It determines the main physiological and biological elements of the system (patient attributes) that are most significant in interindividual variability of clearance. The E H

Cited by 32 publications

References 16 publications

First‐Pass CYP3A‐Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates

First‐Pass CYP3A‐Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates

PBPK Model of Morphine Incorporating Developmental Changes in Hepatic OCT1 and UGT2B7 Proteins to Explain the Variability in Clearances in Neonates and Small Infants

Utilizing Pediatric Physiologically Based Pharmacokinetic Models to Examine Factors That Contribute to Methadone Pharmacokinetic Variability in Neonatal Abstinence Syndrome Patients

Contact Info

Product

Resources

About