Inactive metabolite

Time to peak plasma concentration depends on the rate of IV dosing but is usually achieved in 45—90 seconds. Therapeutic plasma concentrations are 1.5—5.0 )J.g/mL, and concentrations above 5 )J.g/mL maybe toxic. The elimination half-life after a bolus iv dose is 8 min the elimination half-life after a 24 h iv infusion is about 100 min. The dmg is eliminated by the kidneys. Ten percent is unchanged and the remainder is in the form of inactive metabolites... 

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). 

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). 

It has been established that both the 17 hydroxy androgens rind estrogens, when administered orally, are quickly converted (o water-soluble inactive metabolites by intestinal bacteria, usually by reactions at the 17 position. It is this inactivation process that is largely responsible for the low-order oral potency observed with these agents. Incorporation of an additional car-l)on atom at the 17 position should serve to make the now tertiary alcohol less susceptible to metabolic attack and thus potentially confer oral activity to these derivatives. 

German investigators (Brock et al) worked on the creation of alkylating pro-drugs that have cytostatic activity after specific biotransformation in the tumor tissue. Cyclophosphamide (CTX) has well pronounced antitumor activity with the broadest spectrum. It is metabolized to the cytotoxic phosphoamide mustard. In normal tissues with high enzyme level cyclophosphamide is converted to its inactive metabolites (Fig. 2). These differences in biotransformation can explain the relative selectivity of cyclophosphamide towards... 

Cyclooxygenases. Figure 1 Pathways for the formation of prostanoids from arachidonic acid. Arachidonic acid is converted by cyclooxygenase to endoperoxides, which are acted upon by various synthesases to form the prostanoids. Prostacyclin and thromboxane are relatively unstable and break down rapidly to form the inactive metabolites 6-oxo-PGF1a and thromboxane B2, respectively. 

Although MR also binds glucocorticoids, its main ligand in classical mineralocorticoid target tissues such as kidney and colon is aldosterone ( d 1.3 nM). This can be granted to the ability of 11 (3-hydioxysteroid dehydrogenase type II (11 (3-HSD II) to convert active cortisol into its inactive metabolite cortisone in these tissues. Since aldosterone is no substrate for this enzyme it can readily bind to MR, leading to exclusive occupation of the receptor by aldosterone. In contrast, no such mechanism exists in brain and presumably... 

Ibuprofen is the most thoroughly researched 2-ary lpropionic acid. It is a relatively weak, non-selective inhibitor of COX. In epidemiological studies, ibuprofen compared to all other conventional NSAIDs, has the lowest relative risk of causing severe gastrointestinal side effects. Because of this, ibuprofen is the most frequently used OTC ( over the counter , sale available without prescription) analgesic. Ibuprofen is highly bound to plasma proteins and has a relatively short elimination half-life ( 2 h). It is mainly glucuronidated to inactive metabolites that are eliminated via the kidney. 

Plants contain to some extent less bioavailable forms of vitamin B6, e.g., glycosylates, or biologically inactive metabolites, e.g., e-pyridoxin-lysin-complexes. In addition, the release of vitamin B6 from foods rich in fiber is assumed to be delayed. The bioavailability of vitamin B6 from animal-derived foods is therefore overall higher than from plant-derived foods. Good dietary sources of vitamin B6 include chicken, fish, pork, beans, and pulses [1]. 

In between the above two extremes are the monoamines (1-lOnmol/g) which are preformed and stored in terminals but at much lower concentrations than the amino acids and when released are removed primarily by reuptake for re-use, or intraneuronal metabolism to inactive metabolites. Thus the appropriate synaptic organisation, biochemistry and receptor pharmacology of the NTs also varies in keeping with their function. It is often assumed, incorrectly, that the NTs found in the highest concentration are the most potent. In fact the opposite is true. Those like the amino acids while having high affinity for their receptors have low potency while the peptides found at much lower concentration have high potency but low affinity. 

With the exception of pravastatin which is mainly metabolized by isomerization in the gut to a relatively inactive metabolite, the other statins undergo biotransformation by the cytochrome P-450 system. Therefore, drugs known to inhibit statin metabolism should be used cautiously. The time until maximum effect on lipids for statins is generally 4 to 6 weeks. 

Most of the physiologic activity of thyroid hormones is from the actions of T3. T4 can be thought of primarily as a prohormone. Eighty percent of needed T3 is derived from the conversion of T4 to T3 in peripheral tissue under the influence of tissue deiodinases. These deiodinases allow end organs to produce the amount of T3 needed to control local metabolic functions. These enzymes also catabolize T3 and T4 to biologically inactive metabolites. Thyroid hormones bind to intracellular receptors and regulate the transcription of various genes. 

An additional determinate of 5-FU toxicity, regardless of the method of administration, is related to its catabolism and phar-macogenomic factors. Dihydropyrimidine dehydrogenase (DPD) is the main enzyme responsible for the catabolism of 5-FU to inactive metabolites.37 A pharmacogenetic disorder has been identified in which patients have a complete or near-complete... 

Similar to 5-FU, there is a polymorphism associated with irinotecan toxicity. UDP-glucuronosyltransferase (UGT1A1) is an enzyme responsible for the glucuronidation of SN-38 to inactive metabolites, and reduced or deficient levels of this enzyme correlate with irinotecan-induced diarrhea and neutropenia.39 Recently the FDA approved a blood test that detects variations in this gene. This test will assist health care providers in predicting which patients may develop severe toxicities from normal doses of irinotecan and can be ordered prior to patients receiving irinotecan. binotecan is administered as an IV bolus over 60 to 90 minutes in a variety dosing schedules. 

Use of a catalytic cocaine antibody may bypass this potential downfall of the active immunization approach. The enzymatically active catalytic cocaine antibody cleaves cocaine into two inactive metabolites ecognine methyl ester and benzoic acid. The two metabolites are released from the catalytic antibody rendering the antibody free to degrade more cocaine. Because the... 

Inside the cytoplasm of the presynaptic neuron the monoamines are exposed to the mitochondrial outer membrane-bound enzyme monoamine oxidase (MAO). MAO breaks the monoamines down into inactive metabolites before they are taken up into the vesicles. However, if MAO is inhibited, then the monoamines enter the vesicles and are available for release. MAO inhibitors, such as moclobemide, have been used in the treatment of depression, since they increase the availability of noradrenaline and serotonin. Selegiline is used for Parkinson s disease, since it raises dopamine levels. 

The first two antidepressants, iproniazid and imipramine, were developed in the same decade. They were shown to reverse the behavioural and neurochemical effects of reserpine in laboratory rodents, by inhibiting the inactivation of these monoamine transmitters (Leonard, 1985). Iproniazid inhibits MAO (monoamine oxidase), an enzyme located in the presynaptic neuronal terminal which breaks down NA, 5-HT and dopamine into physiologically inactive metabolites. Imipramine inhibits the reuptake of NA and 5-HT from the synaptic cleft by their transporters. Therefore, both of these drugs increase the availability of NA and 5-HT for binding to postsynaptic receptors and, therefore, result in enhanced synaptic transmission. Conversely, lithium, the oldest but still most frequently used mood stabiliser (see below), decreases synaptic NA (and possibly 5-HT) activity, by stimulating their reuptake and reducing the availability of precursor chemicals required in the biosynthesis of second messengers. 

At cellular level, 6-MP is transformed in a number of active and inactive metabolites, and in the bone marrow, the balance between activation and inactivation of 6-MP is the main determinant of its antiproliferative effect. Similar to other antimetabolites, 6-MP is a prodrug lacking any cytotoxic activity and needs to be activated [3] (Figure 14.1). The first step is 6-MP transformation into 6-thioinosine monophosphate (6-TIMP), which is subsequently converted to 6-thioguanine tri-... 

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine dmgs, such as 6-mercaptopurine (6-MP), 6-thioguanine and azathioprine, to inactive metabolites [29-32]. Thiopurines form part of the routine treatment for patients with acute lymphoblastic leukemia, rheumatoid arthritis, and autoimmune diseases such as SLE and Crohn s disease, and are used as an immunosuppressant following organ transplantation. 

Tolbutamide (Y) Orinase 250, 500 1,000-2,000 500-1,000 1,000 3,000 Up to 12 hours Metabolized in liver to inactive metabolites that are renally excreted... 

Glimepiride (Y) Amaryl Short-acting insulin secretagogues 1,2,4 1-2 0.5-1 2 8 24 hours Metabolized in liver to inactive metabolites... 

Repaglinide (N) Prandin 0,5, 1,2 0,5-1 with meals 0.5-1 with meals NA 16 Up to 4 hours Metabolized by CYP 3A4 to inactive metabolites excreted in bile... 

Zolpidem, chemically unrelated to benzodiazepines or barbiturates, acts selectively at the y-aminobutyric acidA (GABAA)-receptor and has minimal anxiolytic and no muscle relaxant or anticonvulsant effects. It is comparable in effectiveness to benzodiazepine hypnotics, and it has little effect on sleep stages. Its duration is approximately 6 to 8 hours, and it is metabolized to inactive metabolites. Common side effects are drowsiness, amnesia, dizziness, headache, and GI complaints. Rebound effects when discontinued and tolerance with prolonged use are minimal, but theoretical concerns about abuse exist. It appears to have minimal effects on next-day psychomotor performance. The usual dose is 10 mg (5 mg in the elderly or those with liver impairment), which can be increased up to 20 mg nightly. Cases of psychotic reactions and sleep-eating have been reported. 

The chemical is rapidly metabolized to an active or inactive metabolite that has a different profile of activity and/or different duration of action than the parent drug. 

Fig. 8.18. Metabolic activation of the prodrug molsidomine (8.159), first by enzymatic hydrolysis of the carbamic acid ester moiety to the inactive metabolite 8.160, followed by spontaneous degradation to the active metabolite 8.161, most likely an NO donor [207] [208]...

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