Effect of hepatic CYP inhibitors on the metabolism of sildenafil and formation of its metabolite, &lt;I&gt;N&lt;/I&gt;-desmethylsildenafil, in rats &lt;I&gt;in vitro&lt;/I&gt; and &lt;I&gt;in vivo&lt;/I&gt;

Bae, Soo Hyeon; Bae, Soo Kyung; Lee, Myung G.

doi:10.1211/jpp/61.12.0008

Cited by 8 publications

(4 citation statements)

References 29 publications

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“…N -Hydroxy- 18 produced by CYP2C19 is associated with methemoglobinema in mammals. Sildenafil (19) − and N -desmethyl- 19 inhibit cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). GMP and its metabolite levels, elevated by endogenous nitric oxide released on sexual stimulation, are maintained high by 19 and its N -desmethyl metabolite inhibition of PDE5 in the penis, leading overall to its use in treating erectile dysfunction.…”

Section: Prodrugsmentioning

confidence: 99%

Why Prodrugs and Propesticides Succeed

Casida

2017

Chem. Res. Toxicol.

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What are the advantages of bioactivation in optimizing drugs and pesticides? Why are there so many prodrugs and propesticides? These questions are examined here by considering compounds selected on the basis of economic value or market success in 2015. The 100 major drugs and 90 major pesticides are divided into ones acting directly and those definitely or possibly requiring bioactivation. Established or candidate prodrugs accounted for 19% of the total drug sales, with corresponding values of 20, 37, and 17% for proinsecticides, proherbicides, and profungicides. The 19 prodrugs acting in humans generally had better pharmacodynamic/pharmacokinetic properties for target enzyme, receptor, tissue, or organ specificity due to their physical properties (lipophilicity and stabilization). Bioactivation usually involved hydrolases or cytochrome P450 oxidation or reduction. Prodrugs considered are neuroactive aripiprazole, eletriptan, desvenlafaxin, lisdexamfetamine, quetiapine, and fesoterodine; cholesterol-lowering atorvastatin, ezetimibe, and fenofibrate; various prodrugs activated by esterases or sulfatases, ciclesonide, oseltamivir, dabigatran; omega-3 fatty acid ethyl esters and esterone sulfate; and five others with various targets (sofosbuvir, fingolimod, clopidogrel, dapsone, and sildenafil). The proinsecticides are the neuroactive chlorpyrifos, thiamethoxam, and indoxacarb, two spiro enol ester inhibitors of acetyl CoA carboxylase (ACCase), and the bacterial protein delta-endotoxin. The proherbicides considered are five ACCase inhibitors including pinoxaden and clethodim, three protox inhibitors (saflufenacil, flumioxazin, and canfentrazone-ethyl), and three with various targets (fluroxypyr, isoxaflutole, and clomazone). The profungicides are prothioconazole, mancozeb, thiophanate-methyl, dazomet, and fosetyl-aluminum. The prodrug and propesticide concept is broadly applicable and has created some of the most selective pharmaceutical and pest control agents, illustrated here by major compounds that partially overcome pharmacokinetic limitations of potency and selectivity in the corresponding direct-acting compounds. The challenges of molecular design extend beyond the target site fit to the bioactivatable precursor and the fascinating chemistry and biology matched against the complexity of life processes.

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Section: Prodrugsmentioning

confidence: 99%

Why Prodrugs and Propesticides Succeed

Casida

2017

Chem. Res. Toxicol.

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“…Chlorzoxazone, a skeletal muscle relaxant once used for the treatment of painful muscle spasm, Significantly slower CL NR (by 47.8%) in LC rats [4] Significantly slower CL (by 52.7% and 16.4%, respectively) in LC and LCD rats [2] 2 CZX (20 mg/kg) [1] CYP2E1 [34,35] Significantly slower CL NR (by 37.5%) in LC rats and comparable CL NR in LCD rats [1] 3 Sildenafil (10 mg/kg) [3] CYP2C11 and 3A1/2 [42] Significantly slower CL (by 64.4% and 54.9%, respectively) in LC and LCD rats [3] 4 Omeprazol (20 mg/kg) [6] CYP1A1/2, 2D1 and 3A1/2 [53] Significantly slower CL NR (by 58.9%) in LC rats [6] 5 DL-Praeruptorin A (5 mg/kg) [7] CYP3A1 and 3A2 [7] Significantly slower CL a (by 46.5%) in LC rats [7] 6 Theophylline (~8 mg/kg) [ primarily undergoes hydroxylation to form 6-hydrochlorzoxazone (OHCZX), which is catalysed via hepatic CYP2E1 in humans and rats [34,35]. It was reported that CZX is metabolized by not only CYP2E1 but also CYP1A2, 2C11, 3A1and 3A2 in rats [36].…”

Section: Chlorzoxazone (Czx; An Intermediate Her Indirect Her 0395 mentioning

confidence: 99%

“…In male SD rats, sildenafil is metabolized via hepatic CYP2C11 and 3A1/2, and N-desmethylsildenafil was formed via CYP2C11 [42]. After i.v.…”

Section: Sildenafil (An Intermediate Her Drug Direct Her 049 [39])mentioning

confidence: 99%

Pharmacokinetic changes of drugs in a rat model of liver cirrhosis induced by dimethylnitrosamine, alone and in combination with diabetes mellitus induced by streptozotocin

Lee

2014

Biopharm & Drug Disp

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Rats with liver cirrhosis induced by N-dimethylnitrosamine (LC) and rats with LC with diabetes mellitus induced by streptozotocin (LCD) have been developed as animal models for human liver cirrhosis and liver cirrhosis with diabetes mellitus, respectively. Changes in the pharmacokinetics of drugs (mainly non-renal clearance, CL NR ) in LC and LCD rats reported in the literature compared with respective control rats were reviewed. This review mainly explains the changes in the CL NR s of drugs (which are mainly metabolized via hepatic microsomal cytochrome P450s, CYPs) in LC and LCD rats, in terms of the changes in in vitro hepatic intrinsic clearance (CL int ; mainly due to the changes in CYPs in the disease state), free (unbound) fraction of a drug in the plasma (f p ) and hepatic blood flow rate (Q H ) depending on the hepatic excretion ratio of the drug. Generally, changes in the CL NR s of drugs in LC and LCD rats could be well explained by the above-mentioned three factors. The mechanism of urinary excretion of drugs (such as glomerular filtration or renal active secretion or reabsorption) in LC and LCD rats is also discussed. The pharmacokinetics of the drugs reported in the LC and LCD rats were scarce in humans. Thus, the present rat data should be extrapolated carefully to humans.

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“…Sildenafil and zidovudine, a vasodilator and HIV antiviral, respectively, were included as model substrates to investigate the potential to improve predictions of PK in RI populations through the use of available preclinical and in vitro data. Sildenafil is metabolized by CYP3A4 and CYP2C9, while glucuronidation mediated by UGT2B7 is the major metabolic pathway for zidovudine [22,23]. The aims of this study were to utilize these model substrates to (1) investigate the impact of changes in protein binding and DME expression/activity on the PK of a model substrate; and (2) to explore the potential of further mechanistic modification based on available preclinical and in vitro data to improve predictions of PK in RI populations.…”

Section: Introductionmentioning

confidence: 99%

Simulation-Based Analysis of the Impact of Renal Impairment on the Pharmacokinetics of Highly Metabolized Compounds

Follman

Morris

2019

Pharmaceutics

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Renal impairment (RI) is a highly prevalent disease which can alter the pharmacokinetics (PK) of xenobiotics, including those that are predominately metabolized. The expression and activity of drug metabolizing enzymes (DMEs) and protein binding of compounds has been demonstrated to be affected in RI. A simulation based approach allows for the characterization of the impact of changes in these factors on the PK of compounds which are highly metabolized and allows for improved prediction of PK in RI. Simulations with physiologically based pharmacokinetic (PBPK) modeling was utilized to define the impact of these factors in PK in RI for a model substrate, nifedipine. Changes in fraction unbound and DME expression/activity had profound effects on PK in RI. Increasing fraction unbound and DME expression resulted in a reduction in exposure of nifedipine, while the reduction of DME activity resulted in an increase in exposure. In vitro and preclinical data were utilized to inform simulations for nifedipine, sildenafil and zidovudine. Increasing fraction unbound and changes in the expression/activity of DMEs led to improved predictions of PK. Further characterization of the impact of RI on these factors is warranted in order to better inform a priori predictions of PK in RI.

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Effect of hepatic CYP inhibitors on the metabolism of sildenafil and formation of its metabolite, <I>N</I>-desmethylsildenafil, in rats <I>in vitro</I> and <I>in vivo</I>

Abstract: Sildenafil is metabolised via hepatic CYP2C11 and 3A1/2, and N-desmethylsildenafil is mainly formed via hepatic CYP2C11 in rats. Thus, rats could be a good model for pharmacokinetic studies of sildenafil and N-desmethylsildenafil in humans.

Cited by 8 publications

References 29 publications

Why Prodrugs and Propesticides Succeed

Why Prodrugs and Propesticides Succeed

Pharmacokinetic changes of drugs in a rat model of liver cirrhosis induced by dimethylnitrosamine, alone and in combination with diabetes mellitus induced by streptozotocin

Simulation-Based Analysis of the Impact of Renal Impairment on the Pharmacokinetics of Highly Metabolized Compounds

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