Plasma metabolism

Anand SS, Kim KB, Padilla S et al (2006) Ontogeny of hepatic and plasma metabolism of deltamethrin in vitro role in age-dependent acute neurootoxicity. Drug Metab Dispos 34 389-397... 

Procarbazine is rapidly absorbed after oral administration and has a plasma half-life of only 10 minutes. The drug crosses the blood-brain barrier, reaching levels in CSF equal to those obtained in plasma. Metabolism is extensive and complex. Urinary excretion accounts for 70% of the procarbazine and its metabolites lost during the first 24 hours after drug administration. 

Pharmacokinetics Rapidly absorbed after PO administration. Protein binding 98%. Primarily distributed in plasma. Metabolized in the liver. Eliminated in feces and urine. Half4ife 2-11 hr. 

Ruel IL, Couture P, Cohn JS, Lamarche (2005) Plasma metabolism of apoB-containing lipoproteins in patients with hepatic lipase deficiency. Atherosclerosis 180 355-366... 

Sohn DR, Kusaka M, Shin SG, et al. Utility of a one-point (3-hour postdose) plasma metabolic ratio as a phenotyping test using metoprolol in two East Asian populations. Ther Drug Monit 1992 14 184—189. 

These findings explain some pharmacokinetic interactions of clobazam with ketoconazole (which inhibits the demethy-lation of clobazam by 70%) and omeprazole (which inhibits the hydroxylation of N-desmethylclobazam by 26%). In addition, in 22 patients with epilepsy who were genotyped for CYP2C19, there was a higher plasma metabolic ratio of N-desmethylclobazam clobazam in patients with one CYP2C19 2 mutated allele than in those with the wild-type genotype. 

Triadimefon is absorbed through dermal, inhalation or oral exposure routes. Triadimefon has a half-life of 2.5 h in blood plasma. Metabolism occurs in the liver resulting mostly in the formation of triadimenol and glucuronic acid conjugates. In mammals, 83-98% is excreted unchanged in the urine and feces within 2-3 days following oral administration. Metabolism of triadimefon occurs more rapidly in male rats compared to females. Radioactivity in male rats was found mainly in feces but more equally distributed between the urine and feces in females. 

Critchfield JW, Keen CL. 1992. Manganese +2 exhibits dynamic binding to multiple ligands in human plasma. Metabolism 41 1087-1092. 

C. Anion gap metabolic acidosis. The normal anion gap of 8-12 mEq/L accounts for unmeasured anions (eg, phosphate, sulfate, and anionic proteins) In the plasma. Metabolic acidosis is usually associated with an elevated anion gap. 

GhiseUi G, Krishnan S, Beigel Y, Gotto AM Jr (1986) Plasma metabolism of apolipoprotein A-IV in humans. J lipid Res 27 813-827... 

Oral and parenteral ketorolac demonstrate similar pharmacokinetics. Parenteral ketorolac has a rapid onset (<1 min IV, <10 min IM) due to its rapid absorption and negligible plasma metabolism. Onset of clinical effects occurs within 15 to 20 minutes. Plasma halflife is approximately 6 hours, intermediate in duration compared with other NSAIDs. Ketorolac undergoes mainly renal metabolism. Over half of an entire ketorolac dose is excreted unchanged in the urine with smaller proportions of minimally active polar metabolites. Elimination is minimally affected by age or hepatic function. Renal insufficiency may decrease the clearance of ketorolac. IM ketorolac demonstrates linear pharmacokinetics. Clearance does not change with chronic dosing. Ketorolac does not cross the blood-... 

Accurate, precise isotope ratio measurements are important in a wide variety of applications, including dating, examination of environmental samples, and studies on drug metabolism. The degree of accuracy and precision required necessitates the use of special isotope mass spectrometers, which mostly use thermal ionization or inductively coupled plasma ionization, often together with multiple ion collectors. 

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). 

Esmolol is iv adrninistered. Maximal P-adrenoceptor blockade occurs in 1 min. Its elimination half-life is about 9 min. EuU recovery from P-adrenoceptor blockade is within 30 min after stopping the infusion. The therapeutic plasma concentrations are 0.4—1.2 lg/mL. It is metabolized by hydrolysis in whole blood by red blood cell esterases resulting in the formation of a primary acid metabohte and free methanol. The metabohte is pharmacologically inactive. The resulting methanol levels are not toxic. Esmolol is 55% bound to plasma protein, the acid metabohte only 10%. Less than 2% of parent dmg and the acid metabohte are excreted by the kidneys. Plasma levels may be elevated and elimination half-hves prolonged in patients with renal disease (41). 

Because digitoxin is a nonpolar, lipophilic glycoside, absorption from the GI tract is complete. About 90% of the dmg in plasma is tightly bound to protein. It is metabolized in the Hver to many metaboHtes, including digoxin which is the only pharmacologically active metaboHte. The dmg is excreted via the bile into feces. The elimination half-life of digitoxin is seven to nine days (87). 

Adenosine is not active orally, but adrninistered as an iv bolus dmg adenosine rapidly eliminates supraventricular tachycardias within 1—2 min after dosing. The dmg slows conduction through the AV node. Adenosine is rapidly removed from the circulation by uptake into red blood ceUs and vascular endothehal ceUs. Thus the plasma half-life is less than 10 s. Adenosine is rapidly metabolized to inosine or adenosine monophosphate and becomes part of the body pool for synthesis of adenosine-triphosphate. 

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). 

Sotalol is rapidly and almost completely (>90%) absorbed. Bioavahabhity of absorbed dmg is 89—100%. Peak plasma levels are achieved in 2—4 h. Sotalol is 50% bound to plasma proteins. Plasma half-life of the compound is about 5.2 h. No metabolites of sotalol have been identified indicating littie metabolism. The dmg is excreted mainly by the kidneys (80—90%) and about 10% is eliminated in the feces. The plasma half-life is prolonged in patients having renal failure. Kinetics of the compound are not affected by changes in liver function (1,2). Sotalol has ah the adverse effects of -adrenoceptor blockers including myocardial depression, bradycardia, transient hypotension, and proarrhythmic effects (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). 

The absorption of metoprolol after po dosing is rapid and complete. The dmg undergoes extensive first-pass metabolism in the liver and only 50% of the po dose in bioavailable. About 12% of the plasma concentration is bound to albumin. The elimination half-life is 3—7 h and less than 5% of the po dose is excreted unchanged in the urine. The excretion of the dmg does not appear to be altered in patients having renal disease (98,99,108). 

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). 

Bevantolol hydrochloride is a moderately lipophilic, long-acting, cardioselective -adrenoceptor blocker. It has no ISA but has membrane-stabilizing activity. The dmg is in use in Europe for the treatment of hypertension and angina. It is rapidly absorbed from the GI tract. Peak plasma levels occur in 1—2 h. It is metabolized extensively in the Hver to a metaboHte that has some ISA. It is excreted by the Hver and the kidneys and excretion is delayed in patients having kidney failure. 

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