Browsing Pathways

Nevirapine is used in the treatment of human immunodeficiency virus (HIV) type 1 (HIV-1) infection. It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that binds to the tyrosines at amino acid residues 181 and 188 of HIV-1 reverse transcriptase. Nevirapine is metabolized in the liver to 2-, 3-, 8-, and 12-hydroxynevirapine by the induction of CYP enzymes, mainly CYP3A4 and CYP2B6. 12-hydroxynevirapine may be further oxidated by ALDH to form 4-carboxynevirapine. These hydroxyl metabolites are glucuronidated by UDP glucuronosyl transferases (UGTs), then exit the cell via the adenosine triphosphate-binding cassette gene ABCC10 for urinary excretion.

Doxepin is a tricyclic antidepressant (TCA) that can be used for treating major depressive disorder and sleep maintenance. Doxepin is metabolized by cytochrome P450 2C19, 1A2, 2C9, 3A4 to form N-desmethyldoxepin, and form (E)-2-hydroxydoxepin by solely cytochrome P450 2D6 in ER of liver.

Acetaminophen (APAP) is metabolized primarily in the liver. Glucuronidation is the main route, accounting for 45-55% of APAP metabolism, and is mediatied by UGT1A1, UGT1A6, UGT1A9, UGT2B15 in the liver and UGT1A10 in the gut. APAP can also by metabolized via sulfation, accounting for 30-35% of the metabolism. In the liver, this step is catalyzed by the sulfotransferases SULT1A1, SULT1A3, SULT1A4, SULT1E1 and SULT2A1. Moreover, APAP can also be activated to form the toxic N-acetyl-p-benzoquinone imine (NAPQI) under the mediation of CYP3A4, CYP2E1, CYP2D6 CYP1A2, CYP2E1 and CYP2A6.

Levomethadyl Acetate (also known as levacetylmethadol or levo-α-acetylmethadol) (LAAM), is a synthetic opioid structurally similar to methadone. It is an opioid agonist that has been used as an analgesic and to treat opioid dependence. Levomethadyl Acetate is metabolized by cytochrome P450 3A4 in two N-demethylation reactions to nor-levomethadyl acetate (nor-LAAM) and subsequently to dinor-levomethadyl acetate (dinor-LAAM).

Tramadol (also named Ultram) is a class of opioid pain medication that used for treating pain. Metabolism of tramadol mainly happened in liver cell. The N-demethylation of tramadol is catalyzed by the cytochrome CYP3A4 and CYP2B6 to form N-Desmethyltramadol, which further metabolized to N,N-Didesmethyltramadol through CYP3A4 and CYP2B6 and to N,O-Didesmethyltramadol through CYP2D6. The O-demethylation of tramadol is catalyzed by the cytochrome CYP2D6 to form O-Desmethyltramadol, which further metabolized to O-Desmethyltramadol glucuronide through UDP-glucuronosyltransferase 2B7 and UDP-glucuronosyltransferase 1-8. O-Desmethyltramadol can also be metabolized to N,O-Didesmethyltramadol through CYP2D6.

Venlafaxine (also named as Effexor or Elafax) is an antidepressant medication, which belongs to the class of serotonin-norepinephrine reuptake inhibitor (SNRI). Venlafaxine is well absorbed into the circulation system. Venlafaxine is also metabolized to N-desmethylvenlafaxine. The N-demethylation is catalyzed by CYP3A4 and CYP2C19. N-desmethylvenlafaxine is a weaker serotonin and norepinephrine reuptake inhibitor. Both O-desmethylvenlafaxine (as potent a serotonin-norepinephrine reuptake inhibitor) and N-desmethylvenlafaxine are further metabolized by CYP2C19, CYP2D6 and/or CYP3A4 to a minor metabolite N,O-didesmethylvenlafaxine that is further metabolized into N,N,O-tridesmethylvenlafaxine or excreted as N,O-didesmethylvenlafaxine gucuronide. Later on, O-desmethylvenlafaxine is exported without any change in chemical structure. Venlafaxine is exported via two transporters: Multidrug resistance protein 1 and ATP-binding cassette sub-family G member 2.

Valproic acid (VPA) is metabolized almost entirely in the liver, via at least there routes: glucuronidation, beta oxidation in the mitochondria, and cytochrome P450 mediated oxidation. The glucuronidation of VPA is mediated by UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7 and UGT2B15. The key CYP-mediated reaction of the VPA metabolic pathway is the generation of 4-ene-VPA by CYP2C9, CYP2A6 and CYP2B6. These three enzymes also catalyze the formation of 4-OH-VPA and 5-OH-VPA. Moreover, CYP2A6 mediates the oxidation of VPA to 3-OH-VPA. Inside the mitochondria, the first step of oxidation is the formation of (VPA-CoA) catalyzed by medium-chain acyl-CoA synthase, followed by the conversion to 2-ene-VPA-CoA through 2-methyl-branched chain acyl-CoA dehydrogenase (ACADSB). 2-ene-VPA-CoA is further converted to 3-hydroxyl-valproyl-VPA (3-OH-VPA-CoA) by an enoyl-CoA hydratase, crotonase (ECSH1) and then 3-OH-VPA-CoA is metabolized to 3-keto-valproyl-CoA (3-oxo-VPA-CoA) through the action of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase. Another route of VPA metabolism in the mitochondria includes the conversion of 4-ene-VPA to 4-ene-VPA-CoA ester catalyzed by ACADSB, followed by a beta-oxidation to form 2,4-diene-VPA-CoA ester. The latter metabolite can furthermore be conjugated to glutathione to form thiol metabolites.

Carbamazepine is a drug used in the treatment of epilepsy, bipolar disorder, trigeminal neuralgia, and other psychiatric disorders. Carbamazepine is almost entirely metabolized in the liver, with the primary metabolic pathway being conversion to 10,11-epoxycarbamazepine. Ring hydroxylation to 2-hydroxycarbamazepine and 3-hydroxycarbamazepine represent a minor metabolic route, presumably though a carbamazepine 2,3-epoxide intermediate. Potential bioactivation occurs via CYP3A4-mediated secondary oxidation of 2-hydroxycarbamazepine to the potentially reactive carbamazepine iminoquinone and of 3-hydroxycarbamazepine to form other reactive metabolites. Radicals can also be formed from metabolism of 3-hydroxycarbamazepine by myeloperoxidase. Oxcarbazepine, an anticonvulsant used primarily in the treatment of epilepsy, is converted to 10,11-dihydroxycarbamazepine via 10-hydroxycarbazepine.

Felbamate is metabolized in the liver. One route of metabolism consists of the hydroxylation to 2-hydroxyfelbamate or p-hydroxyfelbamate, which is catalyzed by CYP2E1 and CYP3A4. Moreover, felbamate can be transformed to 2-phenyl-2-propanediol monocarbamate. This metabolite is then converted to 3-carbamoyl-2phenylpropionaldehyde via alchol dehydrogenase 1A, which in turn can be transformed into three possible metabolites: atropaldehyde, 3-carbamoyl-2-phenylpropionic acid (catalyzed by the dimeric NADP-preferring aldehyde dehydrogenase), and 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one. The latter is further converted by the alcohol dehydrogenase 1A to 5-phenyl-1,3-oxazinane-2,4-dione, which is subsequently transformed to 3-carbamoyl-2-phenylpropionic acid.

Prednisolone is a synthetic glucocorticoid that is used clinically for its anti-inflammatory properties. Prednisolone diffuses passively across the cell membrane, where it binds to glucocorticoid receptors in the cytoplasm. Upon binding, the glucocorticoid receptor (GR) dissociates from heat shock protein 90, and translocate into the nucleus. In the nucleus, GR dimers can bind to glucocorticoid response element (GRE) in the promoter region of anti-inflammatory genes, which activates their transcription. GRs also inhibit transcription of inflammatory mediators by binding to negative GRE (nGRE). GRs further interact with the transcription factors cAMP-responsive element binding protein and NF-kappa-B, and inihibit their activation of inflammatory gene transcription. GRs also recruit histone deacetylase 2 to inflammatory gene loci on DNA, which leads to DNA condensation and suppression of gene expression.