Metabolism peak plasma concentration

Procainamide may be adininistered by iv, intramuscular (im), or po routes. After po dosing, 75—90% of the dmg is absorbed from the GI tract. About 25% of the amount absorbed undergoes first-pass metaboHsm in the fiver. The primary metabolite is A/-acetylprocainamide (NAPA) which has almost the same antiarrhythmic activity as procainamide. This is significant because the plasma concentration of NAPA relative to that of procainamide is 0.5—2.5. In terms of dmg metabolism there are two groups of patients those that rapidly acetylate and those that slowly acetylate procainamide. About 15—20% of the dmg is bound to plasma proteins. Peak plasma concentrations are achieved in 60—90 min. Therapeutic plasma concentrations are 4—10 lg/mL. Plasma half-lives of procainamide and NAPA, which are excreted mainly by the kidneys, are 2.5—4.5 and 6 h, respectively. About 50—60% is excreted as unchanged procainamide (1,2). 

Disopyr mide. Disopyramide phosphate, a phenylacetamide analogue, is a racemic mixture. The dmg can be adininistered po or iv and is useful in the treatment of ventricular and supraventricular arrhythmias (1,2). After po administration, absorption is rapid and nearly complete (83%). Binding to plasma protein is concentration-dependent (35—95%), but at therapeutic concentrations of 2—4 lg/mL, about 50% is protein-bound. Peak plasma concentrations are achieved in 0.5—3 h. The dmg is metabolized in the fiver to a mono-AJ-dealkylated product that has antiarrhythmic activity. The elimination half-life of the dmg is 4—10 h. About 80% of the dose is excreted by the kidneys, 50% is unchanged and 50% as metabolites 15% is excreted into the bile (1,2). 

Phenytoin s absorption is slow and variable yet almost complete absorption eventually occurs after po dosing. More than 90% of the dmg is bound to plasma protein. Peak plasma concentrations are achieved in 1.5—3 h. Therapeutic plasma concentrations are 10—20 lg/mL but using fixed po doses, steady-state levels are achieved in 7—10 days. Phenytoin is metabolized in the fiver to inactive metabolites. The plasma half-life is approximately 22 h. Phenytoin is excreted primarily in the urine as inactive metabolites and <5% as unchanged dmg. It is also eliminated in the feces and in breast milk (1,2). Prolonged po use of phenytoin may result in hirsutism, gingival hyperplasia, and hypersensitivity reactions evidenced by skin rashes, blood dyscrasias, etc... 

Mexifitene is well absorbed from the GI tract and less than 10% undergoes first-pass hepatic metabolism. In plasma, 60—70% of the dmg is protein bound and peak plasma concentrations are achieved in 2—3 h. Therapeutic plasma concentrations are 0.5—2.0 lg/mL. The plasma half-life of mexifitene is 10—12 h in patients having normal renal and hepatic function. Toxic effects are noted at plasma concentrations of 1.5—3.0 lg/mL, although side effects have been noted at therapeutic concentrations. The metabolite, /V-methy1mexi1itene, has some antiarrhythmic activity. About 85% of the dmg is metabolized to inactive metabolites. The kidneys excrete about 10% of the dmg unchanged, the rest as metabolites. Excretion can also occur in the bile and in breast milk (1,2). 

EoUowing po administration moricizine is completely absorbed from the GI tract. The dmg undergoes considerable first-pass hepatic metabolism so that only 30—40% of the dose is bioavailable. Moricizine is extensively (95%) bound to plasma protein, mainly albumin and a -acid glycoprotein. The time to peak plasma concentrations is 0.42—3.90 h. Therapeutic concentrations are 0.06—3.00 ]l/niL. Using radiolabeled moricizine, more than 30 metabolites have been noted but only 12 have been identified. Eight appear in urine. The sulfoxide metabolite is equipotent to the parent compound as an antiarrhythmic. Elimination half-life is 2—6 h for the unchanged dmg and known metabolites, and 84 h for total radioactivity of the labeled dmg (1,2). 

Tocainide is rapidly and well absorbed from the GI tract and undergoes very fitde hepatic first-pass metabolism. Unlike lidocaine which is - 30% bioavailable, tocainide s availability approaches 100% of the administered dose. Eood delays absorption and decreases plasma levels but does not affect bio availability. Less than 10% of the dmg is bound to plasma proteins. Therapeutic plasma concentrations are 3—9 jig/mL. Toxic plasma levels are >10 fig/mL. Peak plasma concentrations are achieved in 0.5—2 h. About 30—40% of tocainide is metabolized in the fiver by deamination and glucuronidation to inactive metabolites. The metabolism is stereoselective and the steady-state plasma concentration of the (3)-(—) enantiomer is about four times that of the (R)-(+) enantiomer. About 50% of the tocainide dose is efirninated by the kidneys unchanged, and the rest is efirninated as metabolites. The elimination half-life of tocainide is about 15 h, and is prolonged in patients with renal disease (1,2,23). 

Encainide is almost completely absorbed from the GI tract. Eood may delay absorption without altering its bioavailabiUty. The dmg is rapidly metabolized in 90% of the patients to two principal metaboUtes, 0-demethylencainide (ODE) and 3-methoxy-O-demethylencainide (MODE), while the other 10% metabolize encainide slowly with Htde or no ODE or MODE formed. Encainide, ODE, and MODE are extensively protein bound 75—80% for encainide and ODE and 92% for MODE. Peak plasma concentrations are achieved in 30—90 min. Therapeutic plasma concentrations are very low the concentrations of ODE and MODE are approximately five times those of encainide. The findings with the metaboUtes are significant because ODE is 2—10 times and MODE, 1—4 times more effective than encainide as antiarrhythmics. The half-Hves for encainide in fast and slow metabolizers is 1—2 h and 6—12 h, respectively. The elimination half-life for ODE is 3—4 h and for MODE 6—12 h in fast metabolizers. Excretion occurs through the Hver and kidneys (1,2). 

Elecainide is weU absorbed and 90% of the po dose is bioavailable. Binding to plasma protein is only 40% and peak plasma concentrations are attained in about 1—6 h. Three to five days may be requited to attain steady-state plasma concentrations when multiple doses are used. Therapeutic plasma concentrations are 0.2—1.0 lg/mL. Elecainide has an elimination half-life of 12—27 h, allowing twice a day dosing. The plasma half-life is increased in patients with renal failure or low cardiac outputs. About 70% of the flecainide in plasma is metabolized by the Hver to two principal metaboUtes. The antiarrhythmic potency of the meta-O-dealkylated metaboUte and the meta-O-dealkylated lactam, relative to that of flecainide is 50 and 10%, respectively. The plasma concentrations of the two metaboUtes relative to that of flecainide are 3—25%. Elecainide is mainly excreted by the kidneys, 30% unchanged, the rest as metaboUtes or conjugates about 5% is excreted in the feces (1,2). 

About 97% of po dose is absorbed from the GI tract. The dmg undergoes extensive first-pass hepatic metaboHsm and only 12% of the po dose is bioavailable. More than 95% is protein bound and peak plasma concentrations are achieved in 2—3 h. Therapeutic plasma concentrations are 0.064—1.044 lg/mL. The dmg is metabolized in the Hver to 5-hyroxypropafenone, which has some antiarrhythmic activity, and to inactive hydroxymethoxy propafenone, glucuronides, and sulfate conjugates. Less than 1% of the po dose is excreted by the kidney unchanged. The elimination half-life is 2—12 h (32). 

The GI absorption of the dmg after po adrninistration is slow and variable with estimates ranging from 20—55%. Once absorbed, 96% of the dmg is bound to plasma proteins and other tissues on the body. Whereas peak plasma concentrations may be achieved in 3—7 h, the onset of antiarrhythmic action may occur in 2—3 days or more. This may result, in part, from distribution to and concentration of the dmg in adipose tissue, Hver, spleen, and lungs. Therapeutic plasma concentrations are 1—2 p.g/mL, although there appears to be no correlation between plasma concentration and antiarrhythmic activity. The plasma half-life after discontinuation of the dmg varies from 13—103 days. The dmg is metabolized in the Hver and the principal metaboHte is desethylamiodarone. The primary route of elimination is through the bile. Less than 1% of the unchanged dmg is excreted in the urine. The dmg can also be eliminated in breast milk and through the skin (1,2). 

Because bretylium is poody absorbed from the GI tract (- 10%), it is adrninistered iv or im. Very litde dmg is protein bound in plasma. Bretylium is taken up by an active transport mechanism into and concentrated in postganglionic nerve terminals of adrenergicahy innervated organs. Peak plasma concentrations after im injections occur in about 30 min. Therapeutic plasma concentrations are 0.5—1.0 p.g/mL. Bretylium is not metabolized and >90% of the dose is excreted by the kidneys as unchanged dmg. The plasma half-life is 4—17 h (1,2). 

After po dosing, verapamil s absorption is rapid and almost complete (>90%). There is extensive first-pass hepatic metabolism and only 10—35% of the po dose is bioavahable. About 90% of the dmg is bound to plasma proteins. Peak plasma concentrations are achieved in 1—2 h, although effects on AV nodal conduction may be apparent in 30 min (1—2 min after iv adrninistration). Therapeutic plasma concentrations are 0.125—0.400 p.g/mL. Verapamil is metabolized in the liver and 12 metabolites have been identified. The principal metabolite, norverapamil, has about 20% of the antiarrhythmic activity of verapamil (3). The plasma half-life after iv infusion is 2—5 h whereas after repeated po doses it is 4.5—12 h. In patients with liver disease the elimination half-life may be increased to 13 h. Approximately 50% of a po dose is excreted as metabolites in the urine in 24 h and 70% within five days. About 16% is excreted in the feces and about 3—4% is excreted as unchanged dmg (1,2). 

Absorption of nadolol after po dosing is variable, averaging about 30%. The presence of food does not affect absorption. There is no hepatic first-pass metabolism and peak plasma concentrations are achieved in 3—4 h after po doses. About 30% of the plasma concentration is protein bound. The elimination half-hfe of nadolol is 20—24 h, allowing once a day dosing. The dmg is excreted unchanged by the kidneys and its excretion is delayed in patients having renal failure (98,99,108). 

Toremifene is an estrogen receptor antagonist. The pharmacokinetics of toremifene are best described by a two-compartment model, with an a half-life of 4 hours and an elimination half-life of 5 days. Peak plasma concentrations are achieved approximately 3 hours after an oral dose. Toremifene is metabolized extensively, with metabolites found primarily in the feces. Toremifene is used for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor-positive or unknown tumors. Toremifene causes hot flashes, vaginal bleeding, thromboembolism, and visual acuity changes. 

Pharmacokinetics Hydralazine is rapidly absorbed after oral use. Half-life is 3 to 7 hours. Protein binding is 87%, and bioavailability is 30% to 50%. Plasma levels vary widely among individuals. Peak plasma concentrations occur 1 to 2 hours after ingestion duration of action is 6 to 12 hours. Hypotensive effects are seen 10 to 20 minutes after parenteral use and last 2 to 4 hours. Slow acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain control of blood pressure. Hydralazine undergoes extensive hepatic metabolism it is excreted in the urine as active drug (12% to 14%) and metabolites. 

Pharmacokinetics Montelukast is rapidly absorbed following oral administration. The mean peak plasma concentration (Cmax) is achieved in 3 to 4 hours (T ax)- The mean oral bioavailability is 64%. Montelukast is more than 99% bound to plasma proteins and is extensively metabolized by the cytochrome P4503A4 and 2C9 pathways. The plasma clearance of montelukast averages 45 mL/min in healthy adults. Montelukast and its metabolites are excreted almost exclusively via the bile. 

Pharmacokinetics Colchicine is rapidly absorbed after oral administration peak plasma concentrations occur in 0.5 to 2 hours. High colchicine concentrations are found in the kidney, liver, and spleen. It is metabolized in the liver. Excretion occurs primarily by biliary and renal routes. 

Pharmacokinetics Absorption is rapid, with peak plasma concentrations occurring in approximately 1 hour following oral administration in fasted subjects. Steady state is achieved after 2 days of multiple twice/day dosing. Levetiracetam is not extensively metabolized. The plasma half-life in adults is approximately 7 hours. Levetiracetam is eliminated from the systemic circulation by renal excretion. 

Pharmacokinetics Following oral administration to healthy volunteers, mean peak plasma concentrations were achieved within 3 hours. Bupropion is 84% bound to human plasma proteins in vitro. Bupropion is extensively metabolized with a mean... 

Absorption/Distribution - Pyrazinamide is well absorbed from the Gl tract and attains peak plasma concentrations within 2 hours. It is widely distributed in body tissues and fluids including the liver, lungs, and cerebrospinal fluid. Pyrizinamide is approximately 10% bound to plasma proteins. Metabolism/Excretion - The half-life is 9 to 10 hours it may be prolonged in patients with impaired renal or hepatic function. 

Olmesartan medoxomil (5) is also a prodrug that is rapidly and completely bioactivated by ester hydrolysis to olmesartan (RNH-6270) during absorption from the gastrointestinal tract (Warner and Jarvis, 2002). Olmesartan is eliminated in a biphasic manner with an elimination half-life of 14 h. The absolute bioavailabihty of olmesartan is 26% and peak plasma concentration is reached in 1 -2 h. Following the rapid and complete conversion of 5 to olmesartan, there is virtually no further metabolism of olmesartan. Olmesartan is eliminated from the bile and kidneys in about a 60 40 ratio. 

Glimepiride is more rapidly absorbed than glicazide with peak plasma concentrations after 2-3 hours. It has very high protein binding of over 99%. Glimepiride is metabolized in the liver with and elimination half-life of 3-6 hours. Its active hydroxy metabolite has an elimination half-life of 5-8 hours and is responsible for part of the hypoglycemic activity of glimepiride. 

Absorption is reduced by food and antacids and the drug should be taken on an empty stomach. Peak plasma concentrations are reached within 1-2 hours. It is widely distributed to all tissues and fluids, including the CNS. INH has a low protein binding of less than 10%. It is eliminated mainly by acetylation in the liver. In rapid acetylators half-lives of 0.5-1.6 hours are found while slow acetylators show half-lives of 2-5 hours. A minor metabolic pathway is via hydroxylation. 

Oral formulations of artemisinin and its derivatives are absorbed rapidly but incompletely. Peak plasma concentrations are reached in 1-2 h. A relative bioavailability of 43% was found for oral artemether compared to intramuscular administration. The absolute bioavailability of artesunate, the only derivative for which an intravenous formulation exists, was about 15%. Artesunate is extensively hydrolyzed to dihydroartemisinin in the gastro-intestinal lumen before first-pass metabolism in the gut wall and liver takes place. Artesunate acts like a prodrug with fast transformation into... 

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