bluuebunny/crossref_metadata_2025 huggingface dataset:
Dopamine
Authors: Gao Chunying
Published: October 2014

Dopamine produces positive chronotropic and inotropic effects on the myocardium, resulting in increased heart rate and cardiac contractility. After male human subjects were infused with [
14
C]‐dopamine, approximately 75% of the infused radioactive dose was metabolized. Major metabolites identified include 3‐methoxy‐4‐hydroxyphenyl acetic acid, 3‐methoxytyramine, 3,4‐dihydroxyphenyl acetic acid, 3,4‐dihydroxy‐phenylethanol, 3‐methoxy‐4‐hydroxyphenylethanol, and their conjugates. The remaining 25% of the infused radioactive dose was identified as norepinephrine. Secondary metabolites included 3,4‐dihydroxymandelic acid, normetanephrine, vanillylmandelic acid, and vanillic acid. 3,4‐Dihydroxyphenylglycol and 3‐methyl‐4‐hydroxyphenylglycol were observed as minor metabolites.
Duloxetine
Authors: Lin Lishan
Published: October 2014

Duloxetine is a serotonin–norepinephrine reuptake inhibitor used to treat depression and urinary incontinence. Metabolism, excretion, and pharmacokinetics of [
14
C]‐duloxetine were examined in healthy human subjects after a single oral dose. Duloxetine was extensively metabolized to numerous metabolites, which are primarily excreted in urine in the conjugated form. The major biotransformation pathways involved hydroxylation of the naphthyl ring at the 4‐, 5‐, or 6‐positions, followed by further hydroxylation, oxidation, and conjugation (sulfate and glucuronide). Furthermore, N‐desmethylation and O‐dealkylation represented minor metabolic pathways. Duloxetine accounted for <3% of the circulating radioactivity. Major metabolites found in plasma were glucuronide conjugates of the hydroxylated metabolites.
Fluvoxamine
Authors: Diao Xingxing
Published: October 2014

Fluvoxamine is an antidepressant of selective serotonin reuptake inhibitors group. Metabolism of fluvoxamine was investigated in human liver microsomes, cDNA‐expressed human CYPs, and human liver cytosol. The aminoethoxy‐ and methoxypentanyl side chains were susceptible to metabolic modifications.
O
‐Demethylated fluvoxamine was formed when fluvoxamine was incubated with pooled human liver microsomes, which was mediated by CYP2D6. Further oxidation of
O
‐demethylfluvoxamine to its carboxylic acid was observed when it was incubated with human liver cytosol, in which alcohol dehydrogenase was involved.
Gabapentin
Authors: Prakash Chandra
Published: October 2014

Gabapentin is used to relieve severe and chronic neuropathic pain. In the dog, gabapentin was metabolized to
N
‐methyl gabapentin (34% of the dose), whereas metabolism in mouse, rat, monkey and human was minimal (<5%). Gabapentin was nearly mainly eliminated via the kidney in all species.
Ilaprazole
Authors: Zhou Xin
Published: October 2014

Ilaprazole is a proton‐pump inhibitor used to treat dyspepsia, peptic ulcer disease, gastroesophageal reflux disease, and duodenal ulcer. The metabolism of ilaprazole was studied in humans. Major circulating metabolites detected were sulfoxide oxidation and reduction metabolites ilaprazole sulfone and ilaprazole sulfide. Their concentrations were much lower than that of the parent drug. In addition to these metabolites, other metabolites were identified in urine. Mono‐ and di‐hydroxylation reactions yielded 12‐hydroxy‐ilaprazole sulfide and 11,12‐dihydroxy‐ilaprazole sulfide, respectively. Opening and reduction of the pyrrol ring yielded 2‐[(4‐methoxy‐3‐methyl)‐2‐pyridinyl]methylthio‐5‐propylamine‐1
H
benzimidazole.
Levonorgestrel
Authors: Yu Jinghua
Published: October 2014

Levonorgestrel is a synthetic progestogen used for contraception. The metabolism and excretion of [
14
C]‐levonorgestrel in female volunteers were studied after a single 1.5‐mg oral dose. Conjugation (sulfates and glucuronides) was the primary metabolic reaction observed. Major urinary metabolites identified included 3α‐hydroxy‐tetrahydrolevonorgestrel (by reduction of the keto moiety), 2α‐hydroxylevonorgestrel, 13‐ethyl‐4‐homogonane‐3,17‐dione (by cleavage of the ethynyl moiety), and their corresponding sulfate and glucuronide conjugates. Minor hydroxylated metabolites included 3β‐hydroxy‐, 3α,16α‐dihydroxy‐, and 3α,16β‐dihydroxy‐tetrahydrolevonorgestrels and 16β‐hydroxylevonorgestrel.
Medroxyprogesterone Acetate
Authors: Zhang Zhi‐Yi
Published: October 2014

Medroxyprogesterone acetate (MPA), a synthetic progestin, is a contraceptive and a therapeutical agent to treat secondary amenorrhea, abnormal uterine bleeding, as well as breast and endometrial cancers. In vitro, the drug underwent cytochromes P450 (CYP)‐mediated hydroxylation at three carbon positions, resulting in the formation of 1‐, 2‐, and 6‐hydroxy‐MPA, and the secondary dihydroxylation and dehydration. 2‐ and 6‐hydroxy‐MPA were the major metabolites. Besides being the substrate for CYPs, particularly CYP3A4, MPA is an inhibitor of CYP2C9 and UGT2B7. In female patients, the principal metabolite appeared to be 6β‐hydroxy‐MPA. In addition to the other major ones seen in vitro, 21‐hydroxy‐MPA, 17α‐acetoxy‐2α,3β‐dihydroxy‐6α‐methylpregn‐4‐en‐20‐one, 6β‐hydroxymethyl‐21‐hydroxy‐MPA, 1‐ene‐MPA, the hydroxylated 1‐ene‐MPA, and the glucuronide conjugates were also detected.
Pravastatin
Authors: Wehr Angela
Published: October 2014

Pravastatin (brand name: Pravachol) is an 3‐hydroxy‐3‐methyl‐glutaryl‐CoA (HMG‐CoA) reductase inhibitor. It is used to reduce cholesterol and triglyceride levels in blood. Pravastatin metabolism and excretion varies by species. Pravastatin is primarily excreted as unchanged drug in the bile of rats, dogs and monkeys, yet is excreted primarily in the urine of humans. Major metabolites of pravastatin include the 3‐alpha‐isomer of pravastatin and a glutathione conjugate. Significant human urinary metabolites, 3‐alpha‐iso‐pravstatin and 6‐epi‐pravastatin, may form from a nonenzymatic‐acid‐catalyzed reaction in the stomach. At least 15 other minor metabolites of pravastatin have been detected.
Sorafenib
Authors: Ding Juefang
Published: October 2014

Sorafenib is an oral protein kinase inhibitor that prevents tumor (kidney and liver) growth by the inhibition of tumor cell proliferation and tumor angiogenesis. The metabolism of sorafenib was investigated in healthy volunteers following a single 100‐mg [
14
C]‐sorafenib tosylate administration. Major circulating metabolite was the pyridine
N
‐oxide, which showed in vitro potency similar to that of the parent drug. Minor metabolites were generated from N‐methylhydroxylation, N‐demethylation, and further N‐oxidation. Glucuronide conjugates (structures not confirmed), accounting for about 15% of the administered dose, were also detected. In vitro experiments showed that CYP3A4 and UGT1A9 were the principal enzymes involved in the metabolism.
Sudoxicam
Authors: Zhang Zhi‐Yi
Published: October 2014

Sudoxicam (SDX), a cyclooxygenase (COX) inhibitor, was a potential nonsteroidal anti‐inflammatory drug (NSAID), and withdrawn from further development due to the hepatotoxicity. In vitro, the compound underwent the oxidative thiazole‐open biotransformation, resulting in the formation of an acylthiourea and the subsequent hydroxylated metabolite. Additionally, the hydrolysis following the initial epoxide formation gave rise to a thiazole‐4,5‐dihydrodiol metabolite. The formation of secondary electrophilic metabolites such as
S
‐oxides from the acylthiourea has been postulated to be associated with SDX‐induced hepatotoxicity. In vivo, the compound exhibited a long plasma half‐lives and small volume of distribution. Metabolic profiles in vivo appeared consistent among the experimental species and human, with the thiazole‐opened, the acylthiourea and thiohydrotoic acid, being the major metabolites.
Bexarotene
Authors: Yu Jinghua
Published: October 2014

Bexarotene is a retinoid compound selectively activating nuclear retinoid receptor. It is used to treat skin lesions of cutaneous T‐cell lymphoma. The metabolism of bexarotene in patients with advanced cancer was investigated following oral doses. Major metabolites identified were 6‐hydroxy‐bexarotene, 7‐hydroxy‐bexarotene, 6‐oxo‐bexarotene, and 7‐oxo‐bexaroten.
Butalbital
Authors: Shao Da
Published: October 2014

Butalbital is a barbiturate with an intermediate duration of action. It is commonly used in combination with other drugs to treat pain and headache. After an oral administration of butalbital in human subjects, it was nearly completely metabolized before renal excretion. The major urinary metabolites included 5‐isobutyl‐5(2,3‐dihydroxypropyl) barbituric acid from the oxidation of the alkene moiety, and 5‐allyl‐5(3‐hydroxy‐2‐methyl‐1‐propyl) barbituric acid from hydroxylation.
Capravirine
Authors: Zhou Xin
Published: October 2014

Capravirine is a nonnucleoside reverse transcriptase inhibitor. Its development as an antiretroviral agent had been discontinued. The metabolism and excretion of [
14
C]‐capravirine were studied in healthy male volunteers receiving a single oral dose of 700 mg. More than 86% of the administered dose was discovered and evenly distributed in urine and feces. Major metabolic reactions observed were sequential oxygenation (hydroxylation, N‐oxidation, and S‐oxidation), and glucuronide/sulfate conjugation.
Cisapride
Authors: Ding Juefang
Published: October 2014

Cisapride is a serotonin 5‐HT
4
receptor agonist used to treat gastric reflux. After a 10‐mg dose to human subjects, 44% was excreted in 24 h in urine and 37% in 35 h in feces. Excretion was complete within 4 days. The primary metabolic pathway was oxidative N‐dealkylation at the piperidine nitrogen to yield norcisapride and 3‐(4‐fluorophenoxy)‐1‐propanol. Norcisapride was the primary urinary and fecal metabolite in humans, and its excretion accounted for 41–45% of the dose. Aromatic hydroxylation accounted for 16% of the dose. Minor metabolites included two lactam metabolites from norcisapride, 3‐F‐4‐OH‐cisapride, 2‐OH‐cisapride, 4‐fluorophenol and its sulfate conjugate, and N
4
‐glucuronide conjugate of cisapride.
Clebopride
Authors: Lin Lishan
Published: October 2014

Clebopride is a dopamine antagonist drug. It is used to treat functional gastrointestinal disorder such as nausea or vomiting. The metabolism of clebopride following a single oral 10‐mg dose was studied in healthy adult male volunteers. Unchanged parent drug was the most abundant compound in human urine. Major metabolites included the hydroxylation at benzyl group to yield carbinolamine and its further N‐dealkylation product, and the piperidine ring hydroxylation/oxidation metabolite (a lactam).
Edoxaban
Authors: Lin Lishan
Published: October 2014

Edoxaban is an anticoagulant drug, which acts as a direct factor Xa inhibitor. The metabolism and excretion in healthy male subjects were studied after an oral administration of 60‐mg [
14
C]‐edoxaban. About 35 and 62% of the administered dose were recovered in urine and feces, respectively. Unchanged edoxaban was the main component in plasma, followed by the metabolite from hydrolytic cleavage of the
N
,
N
‐dimethylcarbamoyl group. Other metabolites were the products by amide hydrolysis, oxidative N‐demethylation of thiazolopyridine ring, N‐demethylation of
N
,
N
‐demethylcarbamoyl group, N‐oxidation of thiazolopyridine ring, and
N
‐glucuronide conjugation of edoxaban.
Nabumetone
Authors: Diao Xingxing
Published: October 2014

Nabumetone is a nonsteroidal anti‐inflammatory drug used for acute and chronic treatments of osteo‐ and rheumatoid arthritides. The metabolism of [
14
C]‐nabumetone (500 mg) was investigated in healthy human subjects after oral drug administration. About 77 and 9% of the radioactivity were recovered in urine and feces, respectively. The parent compound was not detected in plasma and urine, and the major circulating metabolite was 6‐methoxy‐2‐naphthylacetic acid. It is the active metabolite of nabumetone. O‐Demethylation yielded 4‐(6‐hydroxynaphthalen‐2‐yl)butan‐2‐one and 6‐hydroxy‐2‐naphthylacetic acid. The conversion of the keto moiety to alcohol yielded 4‐(6‐methoxy‐2‐naphthyl)butan‐2‐ol and 4‐(6‐hydroxy‐2‐naphthyl)butan‐2‐ol. They were detected in urine. Sulfate and glucuronide conjugates of phase I metabolites were also identified in urine.
Valdecoxib
Authors: Diao Xingxing
Published: October 2014

Valdecoxib is a selective cyclooxygenase‐2 inhibitor used for the treatment of osteoarthritis, dysmenorrhea, or acute pain. Metabolism of [
14
C]‐valdecoxib (50 mg) was investigated in male human subjects after oral administration. The administered radioactivity was recovered 76 and 18% in urine and feces, respectively. Most of the radioactivity in plasma was attributed to valdecoxib and the hydroxymethyl metabolite. Major urinary metabolites included
O
‐glucuronide conjugate of the hydroxymethyl valdecoxib and
N
‐glucuronide conjugate of valdecoxib, accounting for 23 and 20% of the dose, respectively. Other metabolic reactions included N‐hydroxylation of sulfonamide and further glucuronidation, formation of sulfinic acid via oxidative breakdown of the
N
‐hydroxy sulfonamide group. Valdecoxib and
m
‐hydroxylated products were detected in fecal extracts.
Anastrozole
Authors: Yu Yang
Published: October 2014

Anastrozole is an aromatase‐inhibiting drug used for the treatment of breast cancer after surgery and for metastasis in women. The metabolism of [14C]‐anastrozole was studied in human subjects after a single 1‐mg oral administration. Approximately, 60% of the dose was excreted as metabolites and 10% was excreted in urine as the unchanged drug. The primary metabolic pathway of anastrozole included N‐dealkylation to yield triazole, and methyl hydroxylation of a side chain. N‐Conjugation yielded anastrozole
N
‐glucuronide, and O‐conjugation yielded hydroxyanastrozole glucuronide.
Betaxolol
Authors: Ding Juefang
Published: October 2014

Betaxolol is a cardioselective β
1
‐adrenergic blocker used in the treatment of hypertension. Two major metabolic routes of betaxolol in humans were as follows: O‐dealkylation of the cyclopropyl group and subsequent oxidation to the carboxylic acid metabolite 2, N‐dealkylation, oxidative deamination, and oxidation to the acid metabolite 3. A small amount of active metabolite, α‐hydroxybetaxolol, was also detected. Betaxolol and its metabolites were excreted in urine.
Bimatoprost
Authors: Xu Lin
Published: October 2014

Bimatoprost is mainly excreted in urine as unchanged drug. 17‐Phenyl prostaglandin F
2
α is the major metabolite in ocular and other tissues.
Brompheniramine
Authors: Gao Ruina
Published: October 2014

Brompheniramine is a histamine H
1
antagonist. It is commonly used in the treatment of allergies, rhinitis, and urticaria. After oral administration of [
14
C]‐brompheniramine to male human subjects, >52% and 1.5% of the administered radioactivity were recovered in urine and feces, respectively. The parent drug and four metabolites were detected in the urine, including mono‐ and di‐
N
‐demethylated brompheniramine, the carboxylic acid metabolite yielded by oxidative deamination followed by oxidation, and its glycine conjugate.
Buprenorphine
Authors: Xu Lin
Published: October 2014

Buprenorphine is extensively metabolized in human and animal species by the combination of oxidation, N‐dealkylation, and glucuronide conjugation reactions. N‐dealkylated metabolite norbuprenorphine and oxidation metabolite hydroxyl‐buprenorphine are two major metabolites, which are catalyzed by multiple CYPs. The glucuronidation of buprenorphine and norbuprenorphine and subsequent hydrolysis are proposed to cause the enterohepatic circulation of both compounds.
Varenicline
Authors: Xie Cen
Published: October 2014

Varenicline is a partial agonist of the nicotinic acetylcholine receptor. It is used for the treatment of smoking cessation. The metabolism of varenicline was investigated in male healthy volunteers. Unchanged drug was the predominant circulating component. The main route of elimination was urinary, in which the unchanged varenicline accounted for 80% of the dose. Metabolic pathways included
N
‐carbamoyl glucuronidation, hydroxylation, lactam formation, N‐formylation, and
N
‐glucoside conjugation.
Vildagliptin
Authors: Gao Ruina
Published: October 2014

Vildagliptin is an oral antidiabetic drug. It is an inhibitor of dipeptidyl peptidase‐4. The metabolism of vildagliptin was investigated in healthy male subjects after a single oral 100‐mg dose of [
14
C]‐vildagliptin. The major circulating components were unchanged parent and the carboxylic metabolite, accounting 26 and 55% of the total plasma residues, respectively. Four major metabolic reactions were involved in the biotransformation of vildagliptin: hydrolysis of cyano group, amide bond hydrolysis, glucuronide conjugation, and hydroxylation/oxidation and opening of the pyrrolidine ring.
Darunavir
Authors: Xie Cen
Published: October 2014

Darunavir is an inhibitor of the human immunodeficiency virus (HIV) protease. It is commonly coadministered with ritonavir to treat HIV infection. The metabolism and disposition of [
14
C]‐darunavir following a single oral dose of 400 mg was investigated in healthy adult males. After 7 days, 94% of the dose was excreted (82% in feces and 12% in urine), in which 8% of the total radioactivity was the unchanged drug. Major metabolites were formed mainly from carbamate hydrolysis, isobutyl aliphatic hydroxylation, and aniline aromatic hydroxylation. Minor reactions included benzylic aromatic hydroxylation, N‐ or O‐glucuronidation, and combination of the above pathways. Coadministration with low‐dose ritonavir notably reduced the metabolism of darunavir because of the strong CYP3A inhibition by ritonavir, thus leading to an 11‐fold increase in the systemic exposure of darunavir.
Telmisartan
Authors: Diao Xingxing
Published: October 2014

Telmisartan is an angiotensin II receptor antagonist used to treat high blood pressure. Metabolism and excretion of [
14
C]‐telmisartan were evaluated after intravenous 40‐mg and oral 40‐mg administrations to healthy male volunteers. It was rapidly (>98%) excreted via the feces (mainly as unmetabolized parent molecule), whereas urinary excretion accounted for <1% of the initial dose, irrespective of the route of administration. Low level of telmisartan glucuronide conjugate was the only metabolite detected in urine and feces.
Terbinafine
Authors: Zhou Xin
Published: October 2014

Terbinafine is an orally active antifungal agent used to control infections caused by fungus that affect the fingernails or toenails. Metabolism of terbinafine was studied in pediatric patients after a single administration of 125 mg. It was extensively metabolized. The primary metabolites in plasma were carboxyterbinafine (oxidation of a methyl group at the side chain) and N‐desmethyl carboxyterbinafine. Four primary metabolic pathways were observed: N‐demethylation to form desmethylterbinafine and desmethylhydroxyterbinafine; oxidative deamination to form 1‐naphthylaldehyde followed by oxidation to 1‐naphthoic acid or reduction to 1‐naphthalenemethanol; alkyl side chain hydroxylation/oxidation to form hydroxyterbinafine and carboxyterbinafine; and loss of the naththylmethyl group by N‐dealkylation.
Pantoprazole
Authors: Peng Chi‐Chi
Published: October 2014

Pantoprazole (a proton‐pump inhibitor) is used to treat gastroesophageal reflux disease (GERD) and Zollinger‐Ellison syndrome. In vitro and in vivo metabolism of pantoprazole had been studied and its metabolites were identified by LC‐MS and NMR. In vitro, major metabolites of pantoprazole were pantoprazole sulfone, pantoprazole sulfide, 6‐hydroxy‐pantoprazole sulfide, 4′‐O‐demethyl‐pantoprazole sulfide, pantoprazole thioether‐glucoside. In vivo, most of the metbaolites were in the forms of sulfate conjugates and some minor metabolites were as glucuronide conjugates.
Trimebutine
Authors: Zhou Xin
Published: October 2014

Trimebutine is an antimuscarinic and weak μ‐opioid agonist used in the treatment of irritable bowel syndrome and other gastrointestinal disorders. The metabolism of trimebutine was studied in healthy subjects after a single oral 100‐mg trimebutine maleate dose. Major metabolic reactions observed were N‐demethylation and ester hydrolysis. Major metabolites detected in human plasma included
N
‐desmethyl trimebutine,
N
,
N
‐didesmethyl trimebutine, and the product of ester hydrolysis.
Selegiline
Authors: Zhong Kan
Published: October 2014

Selegiline is a selective, irreversible inhibitor of type B monoamine oxidase. It is used to treat early‐stage Parkinson's disease, depression, and senile dementia. Metabolites were identified after oral administration of selegiline hydrochloride to male volunteers. Primary metabolic reactions were N‐dealkylation, β‐carbon hydroxylation, and aryl‐hydroxylation. The parent drug was minor in urine samples, accounting for <1% of the dose. The major metabolite was methamphetamine, accounting for about 37% of the dose.
Ipratropium
Authors: Wehr Angela
Published: October 2014

Ipratropium (brand names: Atrovent, Aerovent, etc.) is a muscarinic receptor antagonist. It is a bronchodilator that relaxes airway muscles and increases air flow to the lung. Ipratropium is rapidly absorbed and eliminated when inhaled. Ipratropium is primarily converted to tropic acid prior to excretion via the intestinal epithelium through the specific secretion of quaternary ammonium salts.
Ropinirole
Authors: Diao Xingxing
Published: October 2014

Ropinirol is a nonergoline dopamine agonist used in the treatment of Parkinson's disease and restless legs syndrome. The disposition and metabolism of ropinirol were investigated in healthy male subjects after an oral 0.1‐mg dose and an intravenous 0.08‐mg dose. The parent drug was extensively metabolized. N‐Dealkylation yielded
N
‐despropyl ropinirol as the major metabolite in humans. Aryl hydroxylation formed the pharmacologically active 7‐hydroxy ropinirol. The
N
‐dealkylated metabolite underwent hydroxylation and oxidative deamination to yield secondary metabolites. Further glucuronide conjugation of the aryl hydroxylation metabolites and a carbamoyl glucuronide derivative was also detected.
Sitagliptin
Authors: Zhong Kan
Published: October 2014

Sitagliptin is a peptidase 4 inhibitor. It is used to treat type 2 diabetes. Metabolism of [
14
C]‐sitagliptin was investigated in healthy male volunteers after a single oral administration of 83 mg. The urinary and fecal excretions recovered were 13 and 87% of the administered dose, respectively. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in feces and 3% in urine). Detected metabolites were the
N
‐sulfate and
N
‐carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization.
Lidocaine
Authors: Penner Natasha
Published: October 2014

Clearance of lidocaine in humans and animals is predominantly metabolic; 4‐hydroxy‐2,6‐dimethylaniline was the major excretory metabolite. Pharmacologically active metabolite 2,6‐xylidine and inactive —OH— 2,6‐xylidineGX are the major circulating metabolites. CYP1A2 has significant involvement in lidocaine biotransformation.
Rizatriptan
Authors: Diao Xingxing
Published: October 2014

Rizatriptan is a 5‐HT agonist used to treat migraine headaches. The absorption and disposition of [
14
C]‐rizatriptan were investigated in healthy human male subjects. After a single oral 10‐mg dose administration, unchanged rizatriptan and its metabolites were excreted mainly in the urine (82% of the dose). Approximately 14% of rizatriptan dose was excreted in urine as intact parent drug. In a high‐dose study (60‐mg p.o.), five metabolites were identified in urine samples. They were rizatriptan‐
N
10
‐oxide, triazolomethyl‐indole‐3‐acetic acid, 6‐hydroxy‐rizatriptan, 6‐hydroxy‐rizatriptan sulfate, and
N
10
‐monodesmethyl‐rizatriptan. Urinary excretion of triazolomethyl‐indole‐3‐acetic acid accounted for 51% of the dose.
Adonifoline
Authors: Chen Meixia
Published: October 2014

Adonifoline is the primary pyrrolizidine alkaloid in
Senecio scandens
Buch.‐Ham. It is used as an infusion to treat oral and pharyngeal infections in China. The glucuronidation of adonifoline was investigated in human liver microsomes with substrate concentration of 100 μM.
N
‐Glucuronidation was the primary metabolic reaction to yield
N
+
‐glucuronide. UGT1A4 is the major enzyme catalyzing this reaction. In vivo metabolism of adonifoline was studied in male rats following a single oral dose. Urinary excretion was the primary route of elimination. Primary metabolic reactions were
N
‐oxidation, hydroxylation, and the hydrolysis of the 12‐membered macrocyclic diester to yield numerous metabolic products. Hydroxylation of adonifoline and its
N
‐oxide yielded at least seven monohydroxylated metabolites. In addition, dehydrogenation of adonifoline formed a reactive intermediate dehydroadonifoline, followed by reacting with water or glutathione to yield dehydrogenated retronecine and GSH adducts. Hydrolysis of the one or both cyclic ester bonds yielded ring opening and cleavage products.
Brivaracetam
Authors: Tu Xiaowei
Published: October 2014

Brivaracetam is a novel synaptic vesicle glycoprotein 2A ligand. It is currently under investigation as an adjunctive treatment of partial‐onset seizures in adults with epilepsy. The metabolism of [
14
C]‐brivaracetam was investigated in healthy volunteers after a single oral administration of 150 mg. In plasma, the unchanged drug was the main compound (almost 90% of the circulating radioactivity). Approximately 97% of the administered radioactivity was recovered in urine and <1% in feces. In urine sample, parent compound accounted for 9% of the dose. The carboxylic acid formed by amide hydrolysis was the major metabolite in urine, which accounted to 34% of the dose. Other major metabolic pathways included hydroxylation of the propyl chain (16% of the dose in urine) and its amide hydrolysis product (15% of the dose in urine). Conjugates with taurine or glucuronic acid and various secondary metabolites were minor.
Clenbuterol
Authors: Tu Xiaowei
Published: October 2014

Clenbuterol is used to treat breathing disorders such as asthma as a decongestant and bronchodilator. The in vivo metabolism of [
14
C]‐clenbuterol was studied in male and female Wistar rats after a single oral dose. Primary metabolic reactions included
N
‐dealkylation (sex‐related differences),
N
‐oxidation, and sulfate conjugation. About 10 metabolites were detected in rat urine. In both male and female rats, in addition to clenbuterol, primary metabolites in urine were 4‐
N
‐hydroxylated metabolite,
N
‐sulfate conjugate, and a glycine conjugate. A metabolic pathway was oxidative deamination/
N
‐dealkylation, and decarboxylation to form dechloroaminobenzoic acid and its glycine conjugate. Another metabolic pathway was
N
‐hydroxylation/oxidation of the amino moiety.
ELZASONAN
Authors: Meng Jian
Published: October 2014

Elzasonan is a selective 5‐hydroxytryptamine 1B and 5‐hydroxytryptamine 1D receptor antagonist used for the treatment of depression. Elzasonan was primarily metabolized via oxidative
N
‐demethylation,
N
‐oxidation, and aryl hydroxylation. In addition, elzasonan was shown to be metabolized to the novel cyclized indole metabolite that underwent subsequent oxidation to form the iminium ion metabolite. Following a single oral administration of [
14
C]‐elzasonan to healthy male human subjects, the parent drug accounted for 20% of circulating radioactivity in plasma. The cyclized indole metabolite was the major drug‐related component in plasma accounted for 65% of the circulating radioactivity. Fecal excretion was the primary elimination route with recovery of 58%. Approximately 21% of radioactivity was excreted in urine. Elzasonan was extensively metabolized, and only 10% radioactivity was excreted unchanged in urine and feces. The major component of the drug‐related material in the excreta was 5‐hydroxyelzasonan, accounted for 34% of the administered dose.
Etoricoxib
Authors: Zhong Kan
Published: October 2014

Etoricoxib is a potent and selective cyclooxygenase‐2 selective inhibitor used for the treatment of osteoarthritis and rheumatoid arthritis. The metabolism of [
14
C]‐etoricoxib was conducted in healthy male subjects following single oral drug administration. In human plasma, 71% of the radioactivity was accounted for the unchanged etoricoxib, and 7–10% of the total activity was 6′‐methylhydroxylation metabolite. Approximately 60% of the administered radioactivity was recovered in urine. Radioactivity in feces accounted for about 20% of the dose. Etoricoxib was extensively metabolized in human with only a minor fraction of unchanged drug (<1% of the dose) detected in excreta. The major metabolite in urine and feces was 6′‐carboxylic acid (about 70% of the total radioactivity). Minor metabolites in urine included 6′‐methylhydroxylation etoricoxib and its
O
‐glucuronide conjugate, and etoricoxib
N
‐oxide and its methylhydroxylation product.
Irofulven
Authors: Zhong Kan
Published: October 2014

Irofulven is an antitumor agent that inhibits the replication of DNA. Patients with advanced tumors were administered by intravenous with [
14
C]‐irofulven. In human plasma, the cyclopropane ring‐opened metabolite and a glutathione conjugate were detected besides the parent. Up to 144 h, 71% and 3% of the administered radioactivity were excreted to urine and feces, respectively. Unchanged irofulven was not detected in urine samples. Metabolic pathways included opening of cyclopropane ring, hydroxylation of methyl groups, reduction of the OH‐group, and glutathione and glucuronide conjugation. In human urine, GSH conjugates and glucuronide conjugates were the primary metabolites of irofulven.
Norgestimate
Authors: Li Xiuli
Published: October 2014

Norgestimate is a synthetic steroid. It is used in combination with ethinyl estradiol for oral contraception. After a single oral dose of [
14
C]‐norgestimate to women, urine and feces were collected and analyzed. Radioactivity recovered in urine and feces was approximately 47% and 37%, respectively. Metabolites identified in urine included norgestrel, 3α,5β‐tetrahydronorgestrel, 2α‐hydroxynorgestrel, 16β‐hydroxynorgestrel and 3,16‐dihydroxy‐5‐tetrahydronorgestrel.
Proxyphylline
Authors: Chen Meixia
Published: October 2014

Proxyphylline is a methylxanthine derivative used for the treatment of obstructive respiratory disease. Metabolism of [
14
C]‐proxyphylline was investigated in volunteers following an intravenous injection. Results showed that about 95% of the radioactive dose was recovered after 3 days. Unchanged proxyphylline accounted for 29% of the urinary radioactivity. Major metabolite identified was 1‐methyl‐7‐(β‐hydroxypropyl)xanthine (
N
‐demethylation), which was responsible for 58% of the urinary radioactivity. Minor metabolites detected were 1‐methyl‐7‐(β‐hydroxypropyl)uric acid (hydroxylation/oxidation), proxyphylline glucuronide, and 1‐methyl‐7‐(β‐hydroxypropyl)xanthine glucuronide.
Rifapentine
Authors: Tu Xiaowei
Published: October 2014

Rifapentine is an antibiotic drug used in the treatment of tuberculosis. The metabolism of [
14
C]‐rifapentine was investigated in healthy male volunteers received a single oral dose of 600 mg. The parent drug and 25‐desacetyl‐rifapentine (
O
‐deacetylation) accounted for essentially the entire plasma radioactivity. Urine was a minor excretion pathway (17% of the dose recovered), and the majority of the radioactive dose was recovered in feces (70%). In feces and urine, the parent drug and three metabolites were detected. 25‐Desacetyl‐rifapentine was the most abundant metabolite in feces and urine, contributing 22% to the profiled radioactivity in feces and 54% in urine. The 3‐formyl derivatives of rifapentine and 25‐desacetyl‐rifapentine, formed by nonenzymatic hydrolysis, were also prominent in feces and, to a lesser extent, in urine.
Verapamil
Authors: Deng Pan
Published: October 2014

Verapamil is an L‐type calcium channel blocker. It is used to treat hypertension, chest pain, and heart rhythm disorders. The metabolism of verapamil was studied in humans after oral administration of [
14
C]‐verapamil. The overall metabolic pathways of verapamil between humans and laboratory animals were consistent. Major metabolites in urine were
N
‐dealkylation (lost of the substuted phenylalkyl moiety), and
N
‐ and
O
‐demethylation products.
Metoclopramide
Authors: Meng Jian
Published: October 2014

Metoclopramide is a dopamine receptor antagonist used for management of gastroparesis or as an antiemetic. After a single oral administration of 20 mg metoclopramide in healthy male volunteers, urine samples were collected over 24‐h period. Metabolites formed by
N
‐dealkylation, aryl hydroxylation, oxidative deamination,
N
‐
O
‐glucuronidation, and
N
‐sulfate conjugation were detected. There was large quantitative variability. The most marked variability was found in levels of N‐sulfate conjugate (21‐fold) and N‐deethylated metoclopramide (16‐fold). This variability might be contributed to the genetic variability of sulfotransferase and CYP2D6.
Mexiletine
Authors: Xu Qiufang
Published: October 2014

Mexiletine is a class IB antiarrhythmic drug. Primary in vitro metabolic pathways observed were aromatic hydroxylation to generate
p
‐hydroxymexiletine and aliphatic hydroxylation to form 2‐hydroxymexiletine. CYP2D6 and, to a lesser extent, CYP1A2 were the major isoforms responsible for the biotransformation of mexiletine. In vivo metabolism of mexiletine was studied in nine healthy volunteers following a single oral 200‐mg dose of mexiletine hydrochloride. Major metabolites detected in the urine were
p
‐hydroxymexiletine, 2‐hydroxymexiletine, and mexiletine
N
‐glucuronide. Deaminized metabolites
p
‐hydroxymexiletine alcohol and hydroxymethyl‐mexiletine alcohol were also detected.
Ruboxistaurin
Authors: Diao Xingxing
Published: October 2014

Ruboxistaurin is a potent protein kinase C inhibitor used for the treatment of diabetic peripheral retinopathy. Disposition of ruboxistaurin was studied in six healthy male subjects after a single oral administration of 64 mg of [
14
C]‐ruboxistaurin. Radioactivity recovered in urine and feces accounted for 4% and 83% of the administered dose, respectively. Ruboxistaurin and its
N
‐desmethylated metabolite contributed to 52% of the radiocarbon in human plasma. In addition, three other metabolites (
N
,
N
‐di‐demethylated, ring hydroxylated, and
N
‐oxide of ruboxistaurin) were also observed in plasma. In human urine, ruboxistaurin accounted for <1% of the radioactive dose. Other major urinary metabolites were
N
‐desmethylated and hydroxylated metabolites.
N
‐Desmethyl ruboxistaurin was the primary metabolite, representing approximately 28% of the radioactive dose eliminated in feces.
Zafirlukast
Authors: Tu Xiaowei
Published: October 2014

Zafirlukast is a peptide leukotriene receptor agonist used for the treatment of asthma. The metabolism of [
14
C]‐zafirlukast was studied in rats, dogs, and mice after oral or intravenous dose administration. Primary metabolic pathways observed were cleavage of the carbamate linkage; mono‐hydroxylation at the cyclopentyl ring, at the
N
‐methyl moiety, and at the methylphenyl ring;
N
‐demethylation; and the cleavage of the sulfonamide linkage. Secondary metabolic reactions include
N
‐acetylation and the subsequent further metabolism by a combination of the above primary metabolic reactions to yield multiple metabolites.
Fluconazole
Authors: Du Jiangbo
Published: October 2014

Fluconazole is a triazole antifungal agent. It is used to treat fungal infections such as oropharyngeal candidiasis and cryptococcal meningitis in AIDS. The disposition and metabolism of [
14
C]‐fluconazole were investigated in three healthy male subjects after a single oral administration (50 mg, 100 μCi). Blood, urine, and feces were collected up to 12 days after administration. Mean total radioactivity excreted in urine and feces represented 91 and 2.3%, respectively. Mean unchanged drug in urine represented 80% of the administered dose. A glucuronide conjugate of unchanged fluconazole and a fluconazole
N
‐oxide (position of
N
‐oxide was not identified) accounted for 7 and 2% of urinary radioactivity, respectively.
Flunarizine
Authors: Ding Juefang
Published: October 2014

Flunarizine is a selective calcium entry blocker used for prophylaxis of severe refractory migraine and symptomatic treatment of vestibular vertigo. In human subcellular fractions, aryl hydroxylation was a major metabolic pathway. In primary cell cultures of human hepatocytes, N‐dealkylation at the 1‐ and 4‐piperazine nitrogen yielded 2 and 6, respectively. Glucuronide conjugate of 2 was also observed. CYP2D6 was involved in the arylhydroxylation of the cinnamyl moiety of flunarizine in human liver microsomes, and CYP2C9 together with 1A1, 1A2, and/or 2A6 mediated the N‐desalkylation at the 1‐ and 4‐positions of the piperazine ring of flunarizine.
Methyldopa
Authors: Meng Jian
Published: October 2014

Methyldopa is a psychoactive drug used as a sympatholytic or antihypertensive treatment. The metabolism of methyldopa in Caco‐2 cell monolayers was similar to that observed in human after oral administration. Conjugation reactions appeared to be the primary metabolic pathway. Major metabolites were methyldopa sulfate, methyldopa glucuronide, 3‐
O
‐methyl‐methyldopa, and its sulfate. The fate of orally administrated 250 mg [
14
C]‐methyldopa (labeled at carbon 3) was studied in healthy male subjects and in hypertensive patients. About 40–52% of the administered radioactivity was excreted via urine. Urinary products identified include methyldopa, methyldopamine, 3,4‐dihydroxyphenylacetone, 3‐
O
‐methyl‐methyldopa, and their conjugates. The major fecal radioactive product was methyldopa, accounted for 30% of dose of radioactivity.
Misoprostol
Authors: Yu Jinghua
Published: October 2014

Misoprostol is nonsteroidal anti‐inflammatory drug. It is used to prevent gastric ulcers, treat missed miscarriage, induce labor, and for early abortion. Metabolism of [3H]‐misoprostol was investigated in male and female rats, mice, dogs, and female monkeys. Rapid ester hydrolysis yielded the free acid as the major metabolite pathway in all test species. In rats, dogs, and monkeys, the acid metabolite was further metabolized to more polar compounds via β‐oxidation of the α‐side chain, ω‐oxidation of the β‐side chain, and reduction of the keto‐group to the prostaglandin F analogs. In rats, misoprostol neither inhibited nor induced drug‐metabolizing enzymes. The primary metabolic pathway of misoprostol in humans was similar to those in animals. No intact misoprostol was found in plasma samples.
Ornidazole
Authors: Du Jiangbo
Published: October 2014

Ornidazole is a third‐generation nitroimidazole derivative with antiprotozoal and antibacterial properties. The metabolism of [
14
C]‐ornidazole was investigated in adult male human subjects. Following an oral administration of 750 mg for human subjects, urine and fecal samples were collected and analyzed. Five metabolites were identified in all three species. Primary metabolic reactions included methyl hydroxylation to yield l‐chloro‐3‐(2‐hydroxymethyl‐5‐nitro‐l‐imidazolyl)‐2‐propanol; N‐dealkylation yielded 2‐methyl‐5‐nitroimidazole,
N
‐(3‐chloro‐2‐hydroxypropyl)acetamide, and acetamide; and dechlorination reaction yielded 3‐(2‐methyl‐5‐nitro‐l‐imidazolyl)‐l,2‐propanediol.
Rofecoxib
Authors: Zhou Xin
Published: October 2014

Rofecoxib was a nonsteroidal anti‐inflammatory drug used to treat osteoarthritis, acute pain conditions, and dysmenorrhea. It had been withdrawn from the market because of safety concerns. The disposition and metabolism of rofecoxib were examined in healthy human subjects by oral administration of 125 mg [
14
C]‐rofecoxib. Rofecoxib underwent extensive metabolism in humans, and very little parent drug was recovered unchanged in urine (<1%). Products resulting from both oxidative and reductive pathways were identified. Major metabolites were rofecoxib‐3′,4′‐trans‐dihydrodiol, 4′‐hydroxyrofecoxib‐
O
‐β‐
d
‐glucuronide, diastereomeric 5‐hydroxyrofecoxib‐
O
‐β‐
d
‐glucuronide conjugates, 5‐hydroxyrofecoxib, rofecoxib‐erythro‐3,4‐dihydrohydroxy acid, and rofecoxib‐threo‐3,4‐dihydrohydroxy acid.
Rotigotine
Authors: Du Jiangbo
Published: October 2014

Rotigotine is a nonergoline dopamine agonist used to treat Parkinson's disease and restless legs syndrome. The metabolism and elimination of [
14
C]‐rotigotine were investigated in healthy male volunteers after intravenous (i.v.) infusion. The total recovery of radioactivity within 216 h after infusion was 95%, in which 71% via kidney and 24% via feces. Rotigotine was extensively metabolized by direct conjugation (rotigotine glucuronide and rotigotine sulfate), N‐desalkylation, and subsequent conjugation. Conjugation of the parent compound was the main biotransformation pathway. Renal elimination of the parent drug was below 1%, whereas the kidneys were the main elimination route for rotigotine metabolites.
Sameridine
Authors: Diao Xingxing
Published: October 2014

Sameridine is both a local anesthetic and a μ‐opioid partial agonist. It is currently under development for the use in surgical anesthesia, mainly administered by intrathecal infusion. The in vitro metabolism of [
14
C]‐sameridine in male rat hepatocytes and liver microsomes was studied. Hydroxylation was the primary metabolic pathway. The ω‐ and ω‐1‐hydroxylation reactions generated 6′‐hydroxysameridine and 5′‐hydroxysameridine, respectively. Furthermore, oxidation of –OH metabolites to keto or carboxylic acid metabolites was also observed: 5′‐keto‐sameridine and three carboxylic acid derivatives. Metabolism was mainly catalyzed by alcohol dehydrogenase, whereas the shortening of the alkyl chain by two carbon atoms was catalyzed by the peroxisomal fatty acid β‐oxidation system. In vivo studies in rats have revealed similar metabolic pathways compared to the in vitro results. In addition, N‐dealkylation of the amide moieties yielded mono‐
N
‐dealkylated metabolites and a di‐
N
‐dealkylated metabolite.
Saxagliptin
Authors: Chen Meixia
Published: October 2014

Saxagliptin is a DPP‐4 inhibitor used to treat type 2 diabetes. The metabolism of saxagliptin in healthy human subjects was investigated. After an oral administration of saxagliptin over a dose range 2.5–50 mg, the hydroxylation metabolite
2
was the major metabolite observed in human plasma and urine. The plasma molar exposure to
2
was about three to seven folds higher than that of saxagliptin in human. In human urine, 7–21% and 16–51% of the dose were eliminated over 48 h as saxagliptin and
2
, respectively. After a single 50‐mg dose of [
14
C]‐saxagliptin, 24, 36, and 75% of the dose were excreted in urine as saxagliptin, metabolite
2
, and total radioactivity, respectively. About 22% of the administered radioactivity was recovered in feces.
Theophylline
Authors: Chen Meixia
Published: October 2014

Theophylline is used as a bronchodilating drug to treat chronic obstructive pulmonary diseases. The metabolism of theophylline involved N‐demethylation and hydroxylation/oxidation in humans. 8‐Hydroxylation/oxidation of theophylline yielded
2
. Metabolite
3
was formed by an initial 3‐N‐demethylation of theophylline followed by a rapid xanthine oxidase mediated 8‐oxidation in humans. Metabolites
5
and
7
were formed by themono‐N‐demethylation in the 1‐ or 3‐positions of theophylline, respectively. The main urinary products after theophylline ingestion were
2
(35%),
3
(19%),
5
(13%), and unchanged theophylline (10%).
Tinidazole
Authors: Du Jiangbo
Published: October 2014

Tinidazole is an antiparasitic drug used against protozoan infections. The pharmacokinetics and metabolism of tinidazole were investigated in two human subjects. Following intravenous (i.v.) infusion of 800 mg [
14
C]‐tinidazole, 44% of the dose was excreted in urine during the first 24 h, increasing to 63% of the dose after 5days, and 12% of the dose was excreted in feces. The parent drug was the major urinary component in 0–120 h (about 32% of the urinary radioactivity). The major metabolite in the 0–12‐h urine samples was ethyl 2‐(5‐hydroxy‐2‐methyl‐4‐nitrol‐imidazolyl)ethylsulfone (about 30% of urinary radioactivity). The formation of this metabolite is a novel pathway involving nitro‐group migration during the hydroxylation reaction. These compounds were also present in feces. A minor urinary metabolite was found to be 2‐hydroxymethyltinidazole (about 9% of urinary radioactivity), which was also present in plasma.
Tipranavir
Authors: Diao Xingxing
Published: October 2014

Tipranavir is nonpeptidic protease inhibitor. It is used in combination with antiretroviral drugs to treat HIV‐1‐infected adult patients with evidence of viral replication. The metabolite profile of tipranavir, coadministered with ritonavir, was investigated in nine healthy male volunteers. The volunteers were administered with twice‐daily [
14
C]‐tipranavir and ritonavir at 500 and 200 mg, respectively, and steady‐state concentrations in plasma were achieved by day 7. In addition to parent drug (
1
), three metabolites were characterized, including a glucuronide conjugate and two monohydroxylated metabolites. Unchanged tipranavir was the predominant circulating component, accounting for >98% of plasma radioactivity. Similarly, the primary radioactive component excreted in feces was unchanged tipranavir, accounting for 80% of fecal radioactivity or 54% of the dose. In contrast, the majority of radioactivity in urine was due to the glucuronide conjugate (11% of urine radioactivity or 0.5% of the dose).
Bicifadine
Authors: Zhou Xin
Published: October 2014

Bicifadine is a serotonin‐norepinephrine‐dopamine reuptake inhibitor. It is being developed as an analgesic to treat different pain conditions. Metabolism of [
14
C]‐bicifadine in healthy adult male subjects was studied following a single oral dose of 200 mg. Hydroxylation and oxidation reactions yielded hydroxymethyl bicifadine, bicifadine lactam metabolite, carboxyl bicifadine, and carboxyl bicifadine lactam as the major circulating metabolites. Minor metabolites found in plasma and urine were glucuronide conjugate of carboxyl bicifadine and glucuronide conjugate of carboxyl bicifadine lactam.
Clofarabine
Authors: Xie Cen
Published: October 2014

Clofarabine is a purine nucleoside antimetabolite for the treatment of relapsed or refractory acute lymphoblastic leukemia in children. The metabolism of [
14
C]‐clofarabine was investigated in male rats after a daily intravenous (i.v.) administration. About 77 and 11% of the dose were recovered in urine and feces, respectively, mainly as unchanged clofarabine. The major metabolite detected was 6‐ketoclofarabine (oxidative deamination product). Its formation had been proposed to be extrahepatic, catalyzed by adenosine deaminase. Other minor metabolites included carboxy‐clofarabine (oxidation of the hydroxymethyl moiety), two glucuronide conjugates and two sulfate conjugates of clofarabine, 2‐chloroadenine (N‐dealkylation), and a phosphate conjugate.
Doripenem
Authors: Xie Cen
Published: October 2014

Doripenem is an ultra‐broad spectrum antibiotic. It is used to control bacterial infections. The disposition, metabolism, and excretion of [
14
C]‐doripenem were studied in eight healthy males following a single 1‐h intravenous (i.v.) dose of 500 mg. The primary metabolic pathway observed was the cleavage of the β‐lactam ring of doripenem to form the dicarboxylic acid metabolite (
2
). Further oxidation or conjugation of
2
yielded an unidentified hydroxylated metabolite, a taurine conjugate, and a glycine conjugate. In blood circulation, the majority of drug‐related material was attributed to unchanged parent drug and metabolite
2
, accounting for 81 and 13% of the total plasma radioactivity, respectively. Doripenem was primarily excreted as the unchanged drug. Seven days after the infusion, 95% of the administered radioactivity was recovered in urine and <1% in feces.