Primary Site Of Metabolism Research Articles

Assessment of Hepatic Impairment and Implications for Pharmacokinetics of Substance Use Treatment.

Although the liver is the primary site of metabolism and biliary excretion for many medications, data are limited on the liver's pharmacokinetic abilities in cirrhosis. Cirrhosis develops through collagen deposition, eventually culminating in end-stage liver disease that compromises hepatic drug metabolism. Consequently, the US Food and Drug Administration (FDA) recommends evaluating the pharmacokinetics of medications in subjects with hepatic impairment if hepatic metabolism constitutes more than 20% of their elimination or if they have a narrow therapeutic range. A variety of noninvasive indices and radiologic procedures can be employed to assess hepatic drug metabolism and excretion. The Child-Pugh score is the most commonly used scale for assessing hepatic impairment among drugs submitted for US FDA approval. The score, originally developed to guide operative mortality in patients undergoing hepatic resection, has not been modified since its inception 5 decades ago. Furthermore, the score was not originally intended to be a guide for potential dose modification in patients with hepatic impairment. These reasons, in combination with the availability of a variety of new imaging modalities and an enhanced understanding of hepatic biology, should foster the development of novel methods to assess the effect of hepatic impairment on liver drug metabolism.

5-HT2A/5-HT2C Receptor Pharmacology and Intrinsic Clearance of N-Benzylphenethylamines Modified at the Primary Site of Metabolism.

The toxic hallucinogen 25B-NBOMe is very rapidly degraded by human liver microsomes and has low oral bioavailability. Herein we report on the synthesis, microsomal stability, and 5-HT2A/5-HT2C receptor profile of novel analogues of 25B-NBOMe modified at the primary site of metabolism. Although microsomal stability could be increased while maintaining potent 5-HT2 receptor agonist properties, all analogues had an intrinsic clearance above 1.3 L/kg/h predictive of high first-pass metabolism.

A case study on quantitative in vitro to in vivo extrapolation for environmental esters: Methyl-, propyl- and butylparaben.

Parabens have been reported as potential endocrine disrupters and are widely used in consumer projects including cosmetics, foods and pharmaceuticals. We report on the development of a PBPK model for methyl-, propyl-, and butylparaben. The model was parameterized through a combination of QSAR for tissue solubility and quantitative in vitro to in vivo extrapolation (IVIVE) for hydrolysis in portals of entry including intestine and skin as well as in the primary site of metabolism, the liver. Overall, the model provided very good agreement with published time-course data in blood and urine from controlled dosing studies in rat and human, and demonstrates the potential value of quantitative IVIVE in expanding the use of human biomonitoring data in safety assessment. An in vitro based cumulative margin of safety (MOS) was calculated by comparing the effective concentrations from an in vitro assay of estrogenicity to the free paraben concentrations predicted by the model to be associated with the 95th percentile urine concentrations reported in NHANES (2009-2010 collection period). The calculated MOS for adult females was 108, whereas the MOS for males was 444.

Use of Benzodiazepines as Anxiolytics in Neonates

Few controlled trials exist to demonstrate the efficacy and the risks of pharmacologic agents used in treating pediatric, and more specifically neonatal patients. It is not different for the central nervous system altering class of drugs, benzodiazepines (BZDs). Little information is known about the long-term effects of BZDs use in neonates as anxiolytics and sedatives causing trepidation with their use in the clinical setting. Insufficient data related to the use of BZDs result in a lack of clear recommendations to guide caregivers at the bedside on the safest administration patterns to avoid long-term adverse effects. However, caring for ill neonates, in particular surgical patients and infants requiring prolonged hospitalizations, necessitates the use of these agents. A literature search within the electronic database, PubMed, of English language, full-text articles published between 2007 and 2012 was undertaken to determine the state of the science regarding the use of BZDs in neonates. These medications cause unwanted effects in neonates with immature hepatic function (primary site of metabolism) and during a developmental period of tremendous neuroplasticity. It benefits caregivers to recognize the need for improved monitoring of stress experienced by infants in the NICU and understand the impact of prolonged agitation and subacute pain on infant development.

Metabolism of Bis(4-fluorobenzyl)trisulfide and Its Formation of Hemoglobin Adduct in Rat Erythrocytes

Bis(4-fluorobenzyl)trisulfide (BFBTS) is a promising new antitumor agent under investigation. It was metabolized rapidly in vivo in rat, but the metabolic fate and primary site of metabolism have not been clarified. In this study, we investigated the role of blood in the metabolism of BFBTS and compared the BFBTS metabolic potencies in whole blood, plasma, and red blood cells (RBCs) in vitro. Three major metabolites of BFBTS [bis(4-fluorobenzyl)disulfide, para-fluorobenzyl-mercaptan, and para-fluorobenzoic acid] were detected in RBCs and whole blood. Significant metabolism of BFBTS was observed in RBCs that were identified as the primary site of BFBTS metabolism. Thiols, including endogenous thiols and hemoglobin, were proven to be the critical factor in BFBTS metabolism. S-Fluorobenzylmercaptocysteine Hb (hemoglobin) adducts were characterized in vitro at BFBTS concentration of 250 μM and higher, whereas such Hb adducts were not detected in RBCs from Sprague-Dawley rats receiving a single intravenous injection of BFBTS at a high dose of 50 mg/kg. Liquid chromatography-tandem mass spectrometry results revealed that adduction induced by BFBTS was prone to take place at Cys125 of globin β chains. Otherwise, glutathionylation of Hb was also observed that may be attributed to the oxidative effect of BFBTS. In summary, BFBTS was unstable when it met with thiols, and RBCs were the main site of BFBTS metabolism. Hb adducts induced by BFBTS could be detected in vitro at high concentration but not in vivo even at high dose.

Aprotinin concentration varies significantly according to cardiopulmonary bypass conditions

Although aprotinin is partially excreted unchanged in the urine, its primary site of metabolism is in the renal lysosomes following proximal tubule resorption. This study tested the hypothesis that plasma aprotinin concentration varies with cardiopulmonary bypass conditions. Thirty-two piglets (weight 13.2 +/- 1.9 kg) received an aprotinin initial dose of 30,000 KIU/kg, a maintenance infusion of 10,000 KIU/kg/h, with a cardiopulmonary bypass (CPB) prime of 30,000 KIU/kg. Aprotinin infusion was terminated at the end of CPB and stopped during hypothermic circulatory arrest (HCA). Piglets were randomized to four groups (n = 8 per group): HCA, 60-minute period at 15 degrees C; low-flow (LF), 10 mL/kg/min low-flow CPB at 25 degrees C; full flow (FF), full flow CPB at 37 degrees C; control at 37 degrees C without CPB. Blood samples were collected at 7 time points: after induction of anesthesia (baseline), after initial dose, 10, 50 and 115 min after start of CPB, just before end of CPB and 30 min after CPB. Plasma aprotinin levels were determined by modified functional assays. Aprotinin levels in the control group were significantly lower at each point after start of CPB than all groups with CPB (p < .001). In particular, during the reperfusion period, aprotinin levels were higher in HCA and LF groups than FF group (p < .05). Throughout CPB, aprotinin levels in the HCA group remained unchanged (p > .40). Bypass conditions affect plasma aprotinin concentration. Recently reported renal and neurological complications with aprotinin use during CPB may reflect excessive dosing and point to the need for real-time monitoring.

DRUG-INDUCED CHRONIC LIVER DISEASE

Over the past half-century, major strides have been made in the understanding of disease susceptibility, pathogenesis, and therapy. As a result, many new drugs have either replaced or been added to the vast array of existing medications available for the treatment of disease. Because the liver is the primary site of metabolism and biotransformation, it is not surprising that drug-induced hepatic injury is relatively common. Indeed, it has long been known that a number of widely used and generally well-tolerated drugs can cause acute liver injury. Chronic drug-induced liver disease (injury lasting more than 3 months), by contrast, was first described in the 1950s with the identification of a prolonged cholestatic illness related to chlorapromazine use.70 Since that time, several other drugs have been implicated in the cause of chronic hepatic injury. Efforts to accurately define the frequency and spectrum of drug-induced chronic liver disease faces several obstacles. On the one hand, many drugs may cause clinically inapparent liver injury. As a consequence, estimates of the true incidence of drug-induced liver disease may be falsely low. On the other hand, case reports in the literature tend to focus on the most severe or fatal drug-related reactions, creating the impression of a falsely elevated drug-associated morbidity and mortality. Lastly, the potential for drugs to cause liver injury must take into account the intrinsic or predictable ability of the drug to produce injury (e.g., via toxins) as well as host susceptibility factors that may lead to unpredictable injury. Taking these factors into account, recent data suggest that drug-induced liver injury occurs in approximately 1 in 600 to 1 in 3500 hospital admissions.28 Two percent to 5% of hospital admissions for jaundice in the United States are drug-induced, as are between 15% to 30% of instances of fulminant hepatic failure, and 20% to 50% of cases of nonviral chronic hepatitis.26, 28, 41, 55 At present, 500 to 1000 agents have been implicated in the cause of a broad spectrum of liver diseases.32, 103, 120

Metabolism and activation of 7,8-dihydrobenzo[a]pyrene during prostaglandin biosynthesis. Intermediacy of a bay-region epoxide.

A Tween 20-solubilized preparation of prostaglandin endoperoxide synthase has been shown to metabolize 7,8-dihydrobenzo[a]pyrene (H2BP) to a form highly mutagenic to Salmonella typhimurium strain TA98. The arachidonic acid-dependent metabolism of H2BP by microsomal and purified prostaglandin endoperoxide synthase has been studied and the products identified. A spectral investigation of the metabolism indicated the bay-region double bond as the primary site of metabolism. Radiolabeled H2BP was synthesized and incubated with the enzyme preparations and the metabolites were separated by reverse phase high performance liquid chromatography and quantitated by liquid scintillation counting. Radioactive products were characterized by co-chromatography with chemically synthesized standards, UV-visible spectra, and mass spectrometry of acetate derivatives. The major polar products were determined to be trans- and cis-9,10-dihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene and 7,8,9,10-tetrahydrobenzo[a]pyrene-9-one in a ratio of 1:1.2:0.4. The inclusion of 5 mM 3,3,3-trichloropropene-1,2-oxide, an epoxide hydrolase inhibitor, produced the same products but in a ratio of 1:2.3:1.2. Incubations with purified prostaglandin endoperoxide synthase yielded the three products in a ratio of 1:2.8:0.7. The major nonpolar product was identified as benzo[a]pyrene. The polar products of metabolism, the effects of 3,3,3-trichloropropene-1,2-oxide on their distribution, and the detection of a mutagenic intermediate support the conclusion that H2BP is co-oxygenated during prostaglandin biosynthesis to 9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.