Pharmacodynamic studies with (-)-3-phenoxy-N-methylmorphinan in rats

Analgesia and brain and plasma concentrations of (-)-3-phenoxy-N-methylmorphinan (PMM) and its metabolites were determined in rats administered 50 mg/kg of 3H-labeled PMM p.o., an approximate ED50. Unchanged PMM and two active metabolites, levorphanol and a different phenol, p-hydroxylated on the 3-phenoxy group (pOH-PMM), were present in brain at concentrations greater than in plasma. Analgesia was observed from 1 to 6 hr and was associated with brain concentrations of 400-1400 ng/g of PMM, 190-300 ng/g of pOH-PMM, and 16-27 ng/g of levorphanol. The presence of 58% of the administered dose as unchanged PMM in the gastrointestinal tract at 6 hr may reflect slow absorption and explain the persisting brain concentrations of PMM and its metabolites as well as the prolonged analgesia. Analgesia may have been due to the presence in brain of only PMM, pOH-PMM or levorphanol, or to the combined activity of two or three of these substances. Administration of the approximate ED50 of 3H-labeled levorphanol (0.1 mg/kg, s.c., or 6 mg/kg, p.o.) resulted in brain levorphanol concentrations (11-18 ng/g) close to those observed when PMM was administered p.o. at 50 mg/kg. After administration of an approximate subcutaneous ED50 of [3H]pOH-PMM of 24 mg/kg, the brains contained pOH-PMM (1500-4100 ng/g) and levorphanol (60-100 ng/g); these levorphanol concentrations were higher than those found after administration of the approximate ED50 of PMM or levorphanol. The findings indicate that brain levorphanol concentrations resulting from administration of PMM or pOH-PMM to rats may account for the analgesic activity observed, i.e. that PMM and pOH-PMM may act as prodrugs for levorphanol     

Biotransformation of the ipecac alkaloids cephaeline and emetine from ipecac syrup in rats.

The metabolism of cephaeline and emetine, which are the primary active components of ipecac syrup, were investigated in rats. Cephaeline-6'-O-glucuronide was found to be a biliary metabolite of cephaeline. Cephaeline (6'-O-demethylemetine) and 9-O-demethylemetine were observed to be enzyme-hydrolyzed biliary metabolites of emetine. Cephaeline was conjugated to glucuronide, while emetine was demethylated to cephaeline and 9-0-demethylemetine, and may be conjugated to glucuronides afterwards. Urine, feces and bile were collected from rats within 48 hours following the administration of ipecac syrup containing tritium (3H)--labeled cephaeline or emetine. Metabolites were separated and quantified by thin layer chromatography (TLC) or high-performance liquid chromatography (HPLC). Biliary and urinary excretion rates of 3H-cephaeline were 57.5% and 16.5% of the dose, respectively. Cephaeline-6'-O-glucuronide was comprised 79.5% of biliary radioactivity and 84.3% of urinary radioactivity. Unchanged cephaeline was detected in 42.4% of the dose in feces. Biliary excretion rate of 3H-emetine was 6.9% of the dose. Emetine, cephaeline and 9-0-demethylemetine comprised 5.8%, 43.2% and 13.6% in hydrolyzed bile, respectively. There were no emetine-derived metabolites in urine or feces. The occurrence of unchanged emetine was 6.8% and 19.7% of the dose in urine and feces, respectively.     

The metabolic disposition of aprepitant, a substance P receptor antagonist, in rats and dogs.

The absorption, metabolism, and excretion of [14C]aprepitant, a potent and selective human substance P receptor antagonist for the treatment of chemotherapy-induced nausea and vomiting, was evaluated in rats and dogs. Aprepitant was metabolized extensively and no parent drug was detected in the urine of either species. The elimination of drug-related radioactivity, after i.v. or p.o. administration of [14C]aprepitant, was mainly via biliary excretion in rats and by way of both biliary and urinary excretion in dogs. Aprepitant was the major component in the plasma at the early time points (up to 8 h), and plasma metabolite profiles of aprepitant were qualitatively similar in rats and dogs. Several oxidative metabolites of aprepitant, derived from N-dealkylation, oxidation, and opening of the morpholine ring, were detected in the plasma. Glucuronidation represented an important pathway in the metabolism and excretion of aprepitant in rats and dogs. An acid-labile glucuronide of [14C]aprepitant accounted for approximately 18% of the oral dose in rat bile. The instability of this glucuronide, coupled with its presence in bile but absence in feces, suggested the potential for enterohepatic circulation of aprepitant via this conjugate. In dogs, the glucuronide of [14C]aprepitant, together with four glucuronides derived from phase I metabolites, were present as major metabolites in the bile, accounting collectively for approximately 14% of the radioactive dose over a 4- to 24-h period after i.v. dosing. Two very polar carboxylic acids, namely, 4-fluoro-alpha-hydroxybenzeneacetic acid and 4-fluoro-alpha-oxobenzeneacetic acid, were the predominant drug-related entities in rat and dog urine.     

液相色谱-串联质谱法分析抗肿瘤新药乙烷硒啉在大鼠体内的代谢产物

本研究对抗肿瘤新药1,2-[二(1,2-苯并异硒唑-3(2H)-酮)]乙烷(乙烷硒啉,BBSKE)在大鼠体内的代谢产物进行鉴定。在灌胃给予大鼠单剂量乙烷硒啉200mg·kg-1后,采用液相色谱-串联质谱法(LC-MSn)对大鼠尿液、粪样、胆汁和血浆中的代谢产物进行检测,通过全扫描和选择离子扫描,以及根据多级质谱裂解规律对代谢物的结构进行分析。研究发现在大鼠尿样、粪样、胆汁和血浆中检测到3种Ⅰ相代谢产物和1种Ⅱ相代谢产物,其代谢途径分别为氧化、甲基化、硫甲基化和葡萄糖醛酸化反应,提示乙烷硒啉在大鼠体内的代谢方式可能是通过氧化、甲基化及葡萄糖醛酸化反应形成代谢产物。     

Pharmacokinetics, enterohepatic circulation and biotransformation of [2-3H]-9,9-Dimethylacridane-10-carboxylic acid S-(2-dimethylamino) thiolethyl ester in the rat and dog

Dogs receiving a 7.5 mg/kg oral or i.v. dose of tritium labelled 9,9-dimethylacridane-10-carboxylic acid S-(2-dimethylamino)thiolethyl ester (DMA) as the methane sulfonate salt (DMA-MS) excreted 86-95% of the radioactivity within 6 days. A similar recovery was obtained for rats receiving 300 mg/kg orally of 15 mg/kg i.v. In both species, approximately 66% of the dose was excreted in the feces as metabolites. Absorption of the oral dose was shown to be 80% and 100% for the rat and dog, respectively. Up to 47% of an i.v. dose was excreted in the bile of rats and an efficient enterohepatic circulation process insues. The parent drug is rapidly metabolized in the tissues yielding at least 6 polar metabolites which contribute to relatively long plasma half-lives in the order of 40 h for dogs and 58-90 h for rats. An atypical increase in plasma radioactivity following an i.v. dose could be rationalized in view of these results. Metabolite profiles were examined in plasma, urine, bile and feces and found to be qualitatively similar. Des-methyl-DMA and DMA-N-oxide were identified as two minor metabolites.     

The metabolism of 14C-cibenzoline in dogs and rats

The disposition of the new antiarrhythmic agent cibenzoline (CBZ) (racemic 4,5-dihydro-2-(2,2-diphenylcyclopropyl)-1H-imidazole) in three male dogs was investigated after oral administration of 13.8 mg/kg of 14C-CBZ base. Within 6 days, 60.5 +/- 6.0% of the dose was excreted in urine and 19.2 +/- 4.6% in feces. In 0-24-hr urine, unchanged drug was excreted (41.6% of the dose) as well as the unconjugated 4,5-dehydro metabolite (DHCBZ, 3.7%), conjugated p-hydroxybenzophenone (0.8%, only in one dog), and a phenolic metabolite, p-hydroxycibenzoline (HCBZ) in a rearranged form (RHCBZ) at 5.2% of the dose (free plus conjugated). Studies with synthetic HCBZ indicated that unrearranged HCBZ was excreted and that rearrangement occurred during purification. CBZ from dog urine displayed slight optical activity, based on ORD/CD data, corresponding to an optical purity of 15% of the S-(-)-CBZ, indicating a limited extent of stereoselective metabolism of CBZ in dogs. After an oral 50-mg/kg dose of 14C-CBZ succinate, male rats excreted in 3 days 27.0 +/- 2.8% in urine and 41.5 +/- 2.6% of the dose in feces, and in a repeated experiment 32.1 +/- 1.9% in urine and 54.5 +/- 0.7% in feces. CBZ (7.6%) and DHCBZ (0.2%) were determined in 0-24-hr urine, and CBZ (4.2%) and RHCBZ (4.2% of the dose) were determined in 0-24-hr feces. RHCBZ (3.1%), m-methoxy p-hydroxycibenzoline (8.3%), and p-hydroxybenzophenone (5.3% of the dose) were identified as glucuronide/sulfate conjugates in bile from rats. Evidence that p-hydroxybenzophenone arose from an unstable unidentified metabolite is discussed.     

Study on metabolism of pyridonecarboxylic acid II. Determination of metabolites of (+-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluenesulfonate hydrate (T-3262) in blood, urine, bile, and feces

The fate of (+-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl-1,4- dihyro-4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluenesulfonate hydrate (T-3262) was studied using T-3262 and 14C-T-3262 in various animals. 1. Metabolites in serum and urine were assayed for mouse, rat, rabbit, dog and monkey following oral administration of T-3262. In serum, besides unchanged T-3262 base, T-3262A (N-acetylated) was detected in rat, rabbit and monkey; T-3262B (deamino-hydroxylated) was detected in monkey. In urine, unchanged T-3262 base was excreted mainly. But a few of metabolites (T-3262A, T-3262B, T-3262 glucuronide, T-3262A glucuronide, T-3262B glucuronide, and unknown compound M-1) were detected, and species difference existed in types of metabolites. 2. Metabolites in bile and feces were assayed for mouse and rat following oral administration of T-3262 and 14C-T-3262. Metabolites in bile were similar to the urine, but the volume of T-3262A and T-3262A glucuronide was larger than in urine. In feces, the excreted compounds mainly consisted of unchanged T-3262 base. 3. p-Toluenesulfonic acid, which is the counter acid for T-3262 base, was absorbed following the oral administration of T-3262, and excreted in urine in the unchanged form.     

The urinary excretion of dextromethorphan and three metabolites in dogs and humans

Quantitative data were obtained for the urinary excretion of dextromethorphan (I) and its metabolites in dogs and humans using recently developed gas chromatographic methods. The recovery of I was 2.8% after iv administration in dogs and only 0.7 and 0.1% after ip and po administration, respectively, confirming previous reports of first-pass metabolism. Of the three known metabolites, only (+)-17-methylmorphinan-3-ol and (+)-morphinan-3-ol were present in significant quantities. In four of five human subjects, less than 0.5% of the dose was excreted unchanged after a single oral dose. The same two metabolites accounted for the bulk of excreted material, and they were largely conjugated, probably as the glucuronide.     

Comparative metabolism of radiolabeled muraglitazar in animals and humans by quantitative and qualitative metabolite profiling.

Muraglitazar (Pargluva), a dual alpha/gamma peroxisome proliferator-activated receptor (PPAR) activator, has both glucose- and lipid-lowering effects in animal models and in patients with diabetes. This study describes the in vivo and in vitro comparative metabolism of [(14)C]muraglitazar in rats, dogs, monkeys, and humans by quantitative and qualitative metabolite profiling. Metabolite identification and quantification methods used in these studies included liquid chromatography/mass spectrometry (LC/MS), LC/tandem MS, LC/radiodetection, LC/UV, and a newly described mass defect filtering technique in conjunction with high resolution MS. After oral administration of [(14)C]muraglitazar, absorption was rapid in all species, reaching a concentration peak for parent and total radioactivity in plasma within 1 h. The most abundant component in plasma at all times in all species was the parent drug, and no metabolite was present in greater than 2.5% of the muraglitazar concentrations at 1 h postdose in rats, dogs, and humans. All metabolites observed in human plasma were also present in rats, dogs, or monkeys. Urinary excretion of radioactivity was low (<5% of the dose) in all intact species, and the primary route of elimination was via biliary excretion in rats, monkeys, and humans. Based on recovered doses in urine and bile, muraglitazar showed a very good absorption in rats, monkeys, and humans. The major drug-related components in bile of rats, monkeys, and humans were glucuronides of muraglitazar and its oxidative metabolites. The parent compound was a minor component in bile, suggesting extensive metabolism of the drug. In contrast, the parent drug and oxidative metabolites were the major components in feces, and no glucuronide conjugates were found, suggesting that glucuronide metabolites were excreted in bile and hydrolyzed in the gastrointestinal tract. The metabolites of muraglitazar resulted from both glucuronidation and oxidation. The metabolites in general had greatly reduced activity as PPARalpha/gamma activators relative to muraglitazar. In conclusion, muraglitazar was rapidly absorbed, extensively metabolized through glucuronidation and oxidation, and mainly eliminated in the feces via biliary excretion of glucuronide metabolites in all species studied. Disposition and metabolic pathways were qualitatively similar in rats, dogs, monkeys, and humans.     

Biotransformation of nevirapine, a non-nucleoside HIV-1 reverse transcriptase inhibitor, in mice, rats, rabbits, dogs, monkeys, and chimpanzees.

The study objectives were to characterize the metabolism of nevirapine (NVP) in mouse, rat, rabbit, dog, monkey, and chimpanzee after oral administration of carbon-14-labeled or -unlabeled NVP. Liquid scintillation counting quantitated radioactivity and bile, plasma, urine, and feces were profiled by HPLC/UV diode array and radioactivity detection. Metabolite structures were confirmed by UV spectral and chromatographic retention time comparisons with synthetic metabolite standards, by beta-glucuronidase incubations, and in one case, by direct probe electron impact ionization/mass spectroscopy, chemical ionization/mass spectroscopy, and NMR. NVP was completely absorbed in both sexes of all species except male and female dogs. Parent compound accounted for <6% of total urinary radioactivity and <5.1% of total fecal radioactivity, except in dogs where 41 to 46% of the radioactivity was excreted as parent compound. The drug was extensively metabolized in both sexes of all animal species studied. Oxidation to hydroxylated metabolites occurred before glucuronide conjugation and excretion in urine and feces. Hydroxylated metabolites were 2-, 3-, 8-, and 12-hydroxynevirapine (2-, 3-, 8-, and 12-OHNVP). 4-carboxynevirapine, formed by secondary oxidation of 12-OHNVP, was a major urinary metabolite in all species except the female rat. Glucuronides of the hydroxylated metabolites were major or minor metabolites, depending on the species. Rat plasma profiles differed from urinary profiles with NVP and 12-OHNVP accounting for the majority of the total radioactivity. Dog plasma profiles, however, were similar to the urinary profiles with 12-OHNVP, its glucuronide conjugate, 4-carboxynevirapine, and 3-OHNVP glucuronide being the major metabolites. Overall, the same metabolites are formed in animals as are formed in humans.     

Glucuronidation as a major metabolic clearance pathway of 14c-labeled muraglitazar in humans: metabolic profiles in subjects with or without bile collection.

The metabolism and disposition of 14C-labeled muraglitazar (Pargluva), a novel dual alpha/gamma peroxisome proliferator-activated receptor activator, was investigated in eight healthy male subjects with and without bile collection (groups 1 and 2) after a single 20-mg oral dose. Bile samples were collected for 3 to 8 h after dosing from group 2 subjects in addition to the urine and feces collection. In plasma, the parent compound was the major component, and circulating metabolites, including several glucuronide conjugates, were minor components at all time points. The exposure to parent drug (Cmax and area under the plasma concentration versus time curve) in subjects with bile collection was generally lower than that in subjects without bile collection. The major portion of the radioactive dose was recovered in feces (91% for group 1 and 51% for group 2). In addition, 40% of the dose was recovered in the bile from group 2 subjects. In this 3- to 8-h bile, the glucuronide of muraglitazar (M13, 15% of dose) and the glucuronides of its oxidative metabolites (M17a,b,c, M18a,b,c, and M20, together, 16% of dose) accounted for approximately 80% of the biliary radioactivity; muraglitazar and its O-demethylated metabolite (M15) each accounted for approximately 4% of the dose. In contrast, fecal samples only contained muraglitazar and its oxidative metabolites, suggesting hydrolysis of biliary glucuronides in the intestine before fecal excretion. Thus, the subjects with and without bile collection showed different metabolic profiles of muraglitazar after oral administration, and glucuronidation was not observed as a major pathway of metabolic clearance from subjects with the conventional urine and fecal collection, but was found as a major elimination pathway from subjects with bile collection.     

Studies on the metabolism of propafenone. 3rd Comm.: Isolation of the conjugated metabolites in the dog and identification using fast atom bombardment mass spectrometry

The metabolism and urinary and biliary excretion of propafenone (2-(2'-hydroxy-3'-propylamino-propoxy)-omega-phenyl-propiophenone hydrochloride) were studied in the dog. Approximately 20% of the dose was excreted in 24 h with the urine and about 65% with the bile. Propafenone was extensively metabolized. Less than 4% of the dose was recovered unchanged in urine and bile. The metabolites were mainly excreted as conjugates. Free metabolites accounted for less than 20% of the dose. Separation methods were developed to isolate and purify the conjugated metabolites. Fractionation on an Al2O3-column yielded a sulphate and a glucuronide fraction, further separation and purification was done by TLC and HPLC. Positive and negative ion fast atom bombardment mass spectra (FAB/MS) were obtained of the purified glucuronides. The structures of two hydroxylated propafenone derivatives and two O-methylated catechol-like derivatives were definitely proven by FAB/MS, the glucuronic acid moiety being conjugated to the hydroxyl function in the different aromatic rings. Two isomeric propafenone glucuronides were found in the bile, probably diastereomeric forms of the O-glucuronide. Thus FAB/MS proved to be a complementary method to electron impact ionization mass spectrometry (EI/MS) for studying drug metabolism. The structures of free and conjugated metabolites can be defined from the combination of both mass spectrometric techniques.     

The metabolism and excretion of enzyme-inducing doses of phenobarbital by rats with bile fistulas

The metabolism of enzyme-inducing doses of 14C-phenobarbital injected i. p. into bile duct-cannulated rats has been studied using improved chromatographic separation and quantification techniques. In animals with bile fistulas most of the 14C-phenobarbital was excreted in bile as p-hydroxyphenobarbital conjugated with glucuronic acid. In urine the main substance found was phenobarbital, with significant amounts of p-hydroxyphenobarbital and varying amounts of its glucuronide conjugate. Animals without bile fistulas excreted 80% dose of phenobarbital in the urine; metabolites were free phenobarbital, p-hydroxyphenobarbital and conjugated material. Approx 90% of the conjugated material was the glucuronide. Only free phenobarbital and p-hydroxyphenobarbital were found in the faeces. Animals drinking plain water excreted 50-65% dose of phenobarbital (80 mg/kg) in bile and the remainder mainly in the urine, whereas superhydrated animals (drinking 5% glucose and 0.9% NaCl) excreted 90% of the dose as free phenobarbital in the urine. Phenobarbital is the only labelled material detectable in hepatic tissue and portal, vena caval or aortic blood, which indicates that phenobarbital is the enzyme-inducing substance and that liver and kidney rapidly eliminate all metabolites. Metabolism of phenobarbital in vivo is a complex process involving interaction of hepatic and intestinal metabolism, partial readsorption from the intestinal tract and renal elimination.     

Metabolism and disposition of the dopamine agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin in conscious monkeys after subsequent i.v. oral, and ocular administration

The metabolism of 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437) was investigated in conscious monkeys after subsequent i.v., oral, and ocular administration. The administration of the drug caused some physiological effects, such as bradycardia and sedation of the monkeys. During a collection period of 120 hr, on average 83% was recovered after iv administration and 90% after p.o. dosing. After i.v. administration, 44% was excreted in the bile, as compared to 38% in the urine and about 1% in the feces. After oral administration, bile is the major excretion route, accounting for about 60% of the dose, as compared to 25% in the urine and about 5% in the feces. After ocular administration, on average 62% was recovered after 7 hr, excreted in bile and urine in about equal amounts. All percentages given above reflect the total amount of radioactivity recovered, thus comprising the unchanged drug plus various metabolites. After all three dosing routes, N-0437 was metabolized almost completely prior to elimination. Direct glucuronidation of the phenolic group proved to be the major metabolic pathway of N-0437, comprising about 44% of the dose after i.v. and ocular administration and 72% after oral dosing. Hydroxylation of N-0437 at the position ortho to the phenolic group present yielded a catechol intermediate, which was excreted as a glucuronide and accounted for about 10% of the dose. In the monkey, a clear regioselective preference towards glucuronidation at the 6-position was observed. Besides the glucuronide, the sulfoconjugate of N-0437 was a major metabolite after i.v. and ocular administration, accounting for about 15% of the dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolism and disposition of sulfinalol in laboratory animals

Peak levels of radioactivity in blood occurred 1.0 hr after oral administration of 3H-sulfinalol hydrochloride to rats, dogs, and monkeys. The plasma decay curve for intact sulfinalol in the dog was biphasic, with apparent first-order half-lives of 0.55 and 6.2 hr. Rats excreted 42.5% of the dose in the urine and 31.8% in the feces after 24 hr. Urinary and fecal recovery were 53.8% and 41.2%, respectively, after 10 days for dogs and 57.8% and 38.0%, respectively, after 9 days for monkeys. Free sulfinalol (11.8% of the dose) was the major component in dog feces with lesser amounts of the sulfide and sulfone metabolites, also in the unconjugated form. All metabolites in dog urine were conjugated with glucuronic acid, with sulfinalol (28.5%) and desmethylsulfinalol (8.5%) representing the major constituents, whereas the sulfone and sulfide metabolites were minor ones. Monkey feces contained primarily unconjugated forms of the desmethyl sulfide metabolite (17.0%) and sulfinalol (7.5%); lesser amounts of desmethylsulfinalol and the sulfone metabolite were present. Desmethylsulfinalol (8.7%) and its sulfate (7.0%) and glucuronide (4.0%) conjugates were the major urinary metabolites in the monkey; sulfinalol (1.4%), its glucuronide conjugate (5.1%), the desmethyl sulfide metabolite (and its sulfate conjugate), and the sulfone metabolite were also present.     

The metabolic disposition of etodolac in rats, dogs, and man

The metabolic disposition of etodolac (etodolic acid) was studied after oral and intravenous administration of the 14C-labeled or unlabeled drug to rats and dogs, and after oral administration of the drug to man. In all species, peak serum drug levels were attained within 2 hr after dosing. In rats and dogs, virtually all of the oral dose was absorbed; etodolac represented 95% of the serum radioactivity in rats and 75% in dogs. Serum levels in all species were generally dose-related. The elimination portion of the serum drug concentration/time curves was characterized by several peaks, which in rats were shown to be due to enterohepatic circulation. Tissue distribution studies in rats showed that radioactivity localized primarily in blood vessels, connective tissue, and highly vascularized organs (liver, heart, lung, and kidney) and that the rate of elimination of radioactivity from tissues was similar to that found in the serum. The apparent elimination half-life of etodolac averaged 17 hr in rats, 10 hr in dogs, and 7 hr in man. Etodolac was extensively bound to serum proteins. Liver microsomal cytochrome P-450 levels were unaltered in rats given etodolac daily for 1 week. The primary route of excretion in rats and dogs was via the bile into the feces. Preliminary biotransformation studies in dogs showed the presence of the glucuronide conjugate of etodolac in bile, but not in the urine. Glucuronide conjugates were not seen in the rat. Four hydroxylated metabolites in rat bile were tentatively identified. It was concluded that, in rats and dogs, etodolac is well absorbed, is subject to extensive enterohepatic circulation, undergoes partial biotransformation, and is excreted primarily into the feces.U     

Studies on the metabolism of propafenone. 2nd comm.: studies on the biotransformation in the dog

Following administration of 14C- and 2H-labelled propafenone hydrochloride (2-(2'-hydroxy-3'-propylaminopropoxy)-omega-phenyl-propiophenone hydrochloride) to beagle dogs, the metabolites were isolated from urine and bile and analysed by mass spectrometry. Reference substances were synthesized on the basis of the structures postulated from the mass spectra and compared with the substances isolated from the biological material. Propafenone was absorbed completely following i.d. administration and eliminated mainly with the bile. Within 28 h 10% of the dose was excreted with the urine and 87% with the bile. Propafenone was extensively metabolized. Less than 1% of the dose was recovered as unchanged substance in urine and bile. The urinary and biliary metabolites were almost exclusively conjugated. The main metabolite, accounting for more than 30% of the dose, was propafenone glucuronide, followed by conjugates of hydroxylated propafenone derivatives with glucuronic acid and sulphuric acid. 5-Hydroxy-propafenone, a propafenone derivative hydroxylated in the middle aromatic ring, and a derivative hydroxylated in the omega-phenyl ring each accounted for about 15% of the dose. Besides these monohydroxy metabolites, two other O-methylated catechol-like derivatives, substituted in the different aromatic rings were recovered. The remainder of the metabolic products identified were mainly substances resulting from degradation of the propoxyamine side chain.     

Quantitative determination of the urinary excretion of ketobemidone and four of its metabolites after intravenous and oral administration in man

The urinary excretion of ketobemidone and its metabolites has been quantified in man after intravenous and oral administration. The metabolism of ketobemidone was found to proceed via 4 metabolic pathways: N-demethylation, ring-hydroxylation, O-methylation, and conjugation. The metabolites were isolated and identified after hydrolysis of the corresponding conjugates. A mean total recovery of about 80% of the dose was found in urine as ketobemidone and metabolites after oral and iv administration, conjugated metabolites amounted to 34-68% of the dose. After iv administration the recovery of unchanged ketobemidone in urine was 13-24%, and after oral administration it was 3-10%. Norketobemidone constituted 10-37% of the dose irrespective of route of administration. 4'-Hydroxyketobemidone amounted to 3-12% of the dose. Neither ketobemidone N-oxide nor metabolites formed after reduction of ketobemidone could be detected in the urine. Less than 2% of the dose was found in feces after iv administration.     

Human biliary metabolites of isotretinoin: identification, quantification, synthesis, and biological activity

1. The metabolites of isotretinoin (13-cis-retinoic acid, Accutane) were investigated in the bile of two patients with biliary T-tube drainage after administration of a single, oral, 80-mg dose of 14C-isotretinoin. Radioactivity measurements showed that the two patients excreted 22.7 and 17.1% of the dose in their bile in 4 days. 2. The two major drug-related components in the bile were identified as the glucuronide conjugates of 4-oxo-isotretinoin and 16-hydroxy-isotretinoin. Two minor components were identified as the glucuronide conjugates of isotretinoin and 18-hydroxy-isotretinoin. 3. H.p.l.c. analyses of Glusulase-treated bile samples indicated that the glucuronides of isotretinoin and the two major metabolites accounted for about 48% and 44% of the total radioactivity in the bile of the two patients. 4. Racemic 16-hydroxy-isotretinoin was synthesized and evaluated for its effect on human sebocytes in vitro. This metabolite and the other major metabolites of isotretinoin were less active than isotretinoin in inhibiting the proliferation of the sebocytes.     

Disposition and metabolism of cetrorelix, a potent luteinizing hormone-releasing hormone antagonist, in rats and dogs.

Disposition and metabolism of cetrorelix was studied in intact and bile duct-cannulated rats and dogs after s.c. injection. An s.c. dose of 0.1 mg/kg [(14)C]cetrorelix was rapidly and completely absorbed in rats. T(max) in plasma and most tissues was at 2 h. Radioactivity at the injection site in rats declined to 10% by 24 h. The extent of (14)C absorption in rats calculated from excretion until 264 h was 94%. Exposure of the target organ pituitary gland was demonstrated with a time course similar to plasma but on a higher level. Rats excreted 69.6% of radioactivity via feces and 24. 3% into urine. Excretion was nearly complete within 48 h. No enteral reabsorption was detected. In dogs t(max) in plasma was 1.3 h. (14)C- and cetrorelix-plasma levels were similar until 24 h, indicating a negligible amount of metabolites. A dose of 1 mg/kg in dogs showed an increasing influence of a slow absorption phase (flip-flop). In dogs equal amounts of the (14)C dose were found within 192 h in feces and urine, 46 and 48%, respectively. In urine of both species, only intact cetrorelix was detected. In bile and feces of both species qualitatively the same metabolites were found, characterized as truncated peptides of the parent decapeptide. The major metabolite occurring in bile of both species was the (1-7)heptapeptide. The amounts of the (1-4)tetrapeptide in feces of rats but not in that of dogs increase with time, suggesting additional degradation of the peptide in the gastrointestinal tract of rats by enteric metabolization.