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Praziquantel
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Praziquantel has a plasma elimination half-life of 1–1.5 hours in humans. It undergoes appreciable first-pass hepatic metabolism (Cioli and Pica-Mattoccia, 2003). Metabolism is primarily by the cytochrome P450 3A4 and 2B1 isoforms (Giorgi et al., 2001). Severe hepatic insufficiency can cause a doubling of the elimination half-life to 2.5 hours and a 4- to 5-fold increase in both Cmax and total drug exposure (Mandour et al., 1990; Watt et al., 1991). These pharmacokinetic parameters are increased proportionate to the degree of hepatic dysfunction (el Guiniady et al., 1994) but occur without significant additional toxicity.
Optimising Antiretroviral Therapy Via Pharmacokinetics
Published in Anne George, K. S. Joshy, Mathew Sebastian, Oluwatobi Samuel Oluwafemi, Sabu Thomas, Holistic Approaches to Infectious Diseases, 2017
Like other NNRTIs, rilpivirine binds to the reverse transcriptase enzyme to terminate the viral DNA replication. It is effective against most of the HIV-1 patients who are resistant to other NNRTIs. This is believed to be the result of its internal conformational flexibility and the plasticity of its interaction with the binding site. Relpivirine mainly undergoes oxidative metabolism followed by sulfate conjugation. It causes cytochrome P450 3A4 enzyme induction due to which combination with other drugs should be made carefully. Rilipivirine has better tolerance and only a few CNS side effects compared to other NNRTIs. Adult oral dosage is 25 mg once a day (Lewis, 2000).
Venous anatomy and pathophysiology
Published in Helane S Fronek, The Fundamentals of Phlebology: Venous Disease for Clinicians, 2007
Drugs that inhibit the hepatic enzyme cytochrome P450 3A4 (CYP3A4) interfere with the metabolism of amide local anesthetics, slowing the rate at which they are eliminated from the body. Common drugs that may increase the toxicity of lidocaine and other amide local anesthetics can be found in Table 13.6. For further information regarding lidocaine drug interactions, see http://www.liposuction.com/pharmacology/drug_interact.php.
Bergamottin can be used to assess CYP3A-mediated intestinal first-pass metabolism without affecting P-glycoprotein-mediated efflux in rats
Published in Xenobiotica, 2020
Kei Suzuki, Kazuhiro Taniyama, Takao Aoyama, Yoshiaki Watanabe
During non-clinical drug development, poor systemic exposure to drug candidates after oral dosing is frequently observed. This necessitates the identification of the factors limiting the bioavailability. Cytochrome P450 3A4 (CYP3A4) is the most abundant P450 subfamily in the intestine in addition to the liver in humans (Paine et al., 2006; Shimada et al., 1994; Zhang et al., 1999), and plays a critical role in intestinal first-pass metabolism by acting as an absorption barrier (Zuber et al., 2002). To estimate CYP3A-mediated intestinal first-pass metabolism in rats, investigators typically conduct co-administration studies with CYP3A4 inhibitors such as ketoconazole (Humphreys et al., 2003; Zhang et al., 1998). However, this compound inhibits both intestinal and hepatic CYP3A activities, making it challenging to determine the main contributor to poor bioavailability in the absence of data from intravenous administration studies. Moreover, in addition to CYP3A4 activity, P-glycoprotein (P-gp/ABCB1) is expressed in the gastrointestinal tract and limits the intestinal absorption of orally administered drugs by active efflux. P-gp adds to the complexity of CYP3A studies because it is difficult to determine whether CYP3A4 or P-gp is the major factor in low absorption; most CYP3A4 inhibitors are also likely to attenuate the activity of P-gp. Thus, an inactivator that selectively inhibits intestinal CYP3A activity without having an effect on P-gp would facilitate the investigation of the mechanisms underlying the poor pharmacokinetics of certain drug candidates.
Solubilization of a novel antitumor drug ribociclib in water and ten different organic solvents at different temperatures
Published in Drug Development and Industrial Pharmacy, 2022
Ramadan Al-Shdefat, Mohammad Hailat, Osama Y. Alshogran
Furthermore, RCB shows higher solubility with a decrease in pH and is affected by neither food intake nor the pH of gastric fluids [1]. The reported pH of a 1.0% v/v solution of the succinate salt of the drug substance in distilled water is 5.19. Even, if it has a solubility of about 2.4 mg mL−1 in acidic conditions, RCB succinate complains of low aqueous solubility in neutral media and is reported for a free base of 0.63 mg mL−1 [1,7]. Cytochrome P450 3A4 extensively metabolizes RCB. Therefore, cytochrome P450 3A4 modulators are affected by cytochrome and have limited efflux transport to the brain. On the other hand, high exposure to the RCB is associated with an increased risk of neutropenia [1,7,8]. The solubility and physicochemical data of RCB are rarely available in the literature. The solubility data, solubility parameters, and thermophysical properties of poorly water-soluble drugs in aqueous and organic solvents have a significant role in various industrial processes such as “purification, recrystallization, drug discovery process, pre-formulation studies, and dosage form design” of poorly water-soluble compounds [9–12]. Therefore, this study reports new solubility data of RCB in water and ten different organic solvents namely “methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA), n-butanol (n-BuOH), acetone, propylene glycol (PG), polyethylene glycol-400 (PEG-400), Transcutol-HP (THP), ethyl acetate (EA), and dimethyl sulfoxide (DMSO)” at 293.2–313.2 K and 101.1 kPa. “Apparent thermodynamic analysis” evaluation was performed to predict the dissolution behavior of RCB. The solubility and physicochemical data of RCB reported in this study could be utilized in “purification, recrystallization, drug discovery, pre-formulation studies, and dosage form design” of RCB.
Reckoning γ-Glutamyl-S-allylcysteine as a potential main protease (mpro) inhibitor of novel SARS-CoV-2 virus identified using docking and molecular dynamics simulation
Published in Drug Development and Industrial Pharmacy, 2021
Arun Parashar, Arpit Shukla, Ankush Sharma, Tapan Behl, Dweipayan Goswami, Vineet Mehta
In our study, we used the pkCSM - pharmacokinetics server [47] for predicting the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the top hits (Chloroquine, Cuscohygrine, γ-Glutamyl-S-allylcysteine, Anahygrine and S-allylcystein). This server predicted physiochemical as well as pharmacological properties. Simplified Molecule Input Line Entry Specification (SMILES) of the selected molecules were retrieved from PubChem, followed by uploading them to pkCSM - pharmacokinetics server. The server computed in-vivo absorption parameters like water solubility in the buffer system (SK atomic types, mg/L), Human intestinal absorption (HIA, %), in-vivo Caco2 cell permeability (Human colorectal carcinoma), in-vivo skin permeability (logKp, cm/hour), and in-vivo P-glycoprotein inhibition. We determined the metabolic parameters by using in-vivo Cytochrome P450 2C9 inhibition, in-vivo Cytochrome P450 2C19 inhibition, in-vivo Cytochrome P450 2D6 inhibition, in-vivo Cytochrome P450 3A4 inhibition, in-vivo Cytochrome P450 2D6 substrate, and in-vivo Cytochrome P450 3A4 substrate. For the distribution properties we included tests like, Blood-Brain Barrier (BBB) penetration, Central Nervous System (CNS) permeability and Lipinski’s Rule (Rule of Five). To access the toxicity of compounds, a range of vital endpoints such as, ames test, acute algae toxicity, 2 years carcinogenicity bioassay in rat, 2 years carcinogenicity bioassay in mouse, in-vivo Ames test result in TA100 strain (Metabolic activation by rat liver homogenate) were computed. Moreover, many drugs are often withdrawn at clinical trial stages due to their poorer renal clearance, which makes excretion a very important parameter. Therefore, in this study we also included total renal clearance and renal OCT2 Substrate to identify the excretion efficacy of the molecules under study.