Influence of spironolactone pretreatment on pharmacokinetics and metabolism of digitoxin in rats

Summary The influence of pretreatment with spironolactone (84 mg/kg at 3 days, twice per day) on the tritium levels in plasma, urine and feces of female SD-rats (n=9) was investigated at various time periods after oral administration of 25 g/kg ³H-digitoxin. In plasma, the concentrations of total radioactivity are reduced in pretreated animals to about 20% of tritium levels in control rats, while the half-life of radioactivity in both groups is almost identical, 2.9 days in pretreated rats and 2.8 days in controls. The lower plasma levels of tritium in pretreated rats coincide with a six-fold decrease in the urinary ³H-elimination and a corresponding increase in the fecal excretion. This is due to a higher biliary clearance of tritiated products in the early phase of elimination. The separation of the excretion products by TLC shows that spironolactone pretreatment enhances the splitting of the glycosidic bonds of digitoxin. The amount of digitoxigenin-bis-digitoxoside and of digitoxigenin-mono-digitoxoside excreted in urine and feces within 96 hrs is four and ten times greater than that recovered in control animals, respectively. The formation of the hydroxylation products digoxin and digoxigenin-bis-digitoxoside is decreased from 50% of the total excreted radioactivity in control to 15% in pretreated rats. The conjugation reactions with glucuronic and sulfuric acid are increased after pretreatment with spironolactone. Thus, the effect of spironolactone on digitoxin kinetics is apparently related to an enhancement of the hepatic excretory mechanism as well as to an enhanced metabolism.Supported by the Deutsche Forschungsgemeinschaft.     

Disposition and metabolism of [2-14C]epichlorohydrin after oral administration to rats

A comprehensive disposition and metabolism study of epichlorohydrin (ECH) has not been previously reported. In this study, male Fischer 344 rats were dosed (6 mg/kg) orally with [2-14C]ECH (98% radiochemically pure) as an aqueous solution and killed after 3 days. Approximately 38% of the radioactive dose was exhaled as CO2, 50% was excreted as metabolites in the urine, and 3% was present in the feces. Radioactivity in tissues accounted for the remainder of the administered dose. When expressed per gram of tissue, radioactivity was highest in liver, kidney, and forestomach. The half-life of initial elimination of radioactivity in both the urine and exhaled air was about 2 hr, indicating that ECH was rapidly absorbed and metabolized. The major metabolites in the urine were identified as N-acetyl-S-(3-chloro-2-hydroxypropyl)-L-cysteine and alpha-chlorohydrin, about 36 and 4% of the administered dose, respectively. Finding these metabolites, which have not been previously reported, is consistent with the initial metabolic reactions being conjugation of the epoxide with glutathione and hydration of the epoxide.     

Metabolism and disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin in guinea pigs

Marked interspecies variability exists in the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with the guinea pig being the mammalian species most sensitive to the acute toxicity of TCDD. The metabolism and disposition of TCDD was investigated in guinea pigs for 45 days following a single exposure to purified [3H]TCDD (0.56 microgram/kg, ip). Guinea pigs included in the toxicokinetic study gained body weight, maintained a normal relative body composition, and exhibited no gross signs of toxicity during the 45-day study. Approximately 36% of the dose of TCDD-derived 3H remained in the adipose tissue at 45 days following exposure to [3H]TCDD, while the liver, pelt, and skeletal muscle and carcass each contained about 7% of the administered dose. Although most of the TCDD-derived radioactivity in liver, kidney, perirenal adipose tissue, and skeletal muscle represented unchanged TCDD, from 4 to 28% of the 3H was associated with metabolites of TCDD. This unexpected finding suggests that TCDD metabolites are not efficiently excreted from guinea pigs. The urinary and fecal excretion of TCDD-derived radioactivity followed apparent first-order kinetics, with an elimination half-life of 93.7 +/- 15.5 days (mean +/- SD). HPLC analysis of urine and bile from [3H]TCDD-treated guinea pigs showed that all of the radioactivity represented metabolites of TCDD, indicating that these routes of elimination are dependent on prior metabolism of TCDD. However, 70 to 90% of the radioactivity in fecal samples was found to represent unmetabolized TCDD throughout the 45-day excretion study. The presence of TCDD in feces and its absence in bile suggest that the fecal excretion of unchanged TCDD resulted from the direct intestinal elimination of the lipophilic toxin. Furthermore, the cumulative excretion of TCDD-derived radioactivity over 45 days indicated that 74.3% of the 3H was excreted in feces as unchanged TCDD, while 25.7% of the 3H was excreted in urine and feces as TCDD metabolites. Thus, TCDD is primarily eliminated unchanged in the feces of guinea pigs, indicating that the metabolism of TCDD does not play a major role in the ultimate elimination of the toxin from the guinea pig. This may in part explain the relatively long excretion half-life for TCDD in the guinea pig and may contribute to the remarkable sensitivity of the guinea pig to the acute toxicity of TCDD.     

Hepatobiliary elimination of bendamustin (Cytostasan) in rats.

Biliary excretion of bendamustin (Cytostasan, 5-[bis(2-chloroethyl)amino]-i-methylbenzimidazole-2-butyric acid; 1) and its metabolites was studied in rats after i.v. administration of 14C-1. The most significant finding was the rapid excretion of 1 related radioactivity in the bile occurring shortly after injection. While radioactivity eliminated by bile within 2 h was 41.8%, in the course of subsequent 22 h it amounted only to 3.2%. Bile samples analyzed by TLC indicated that the total amount of radioactivity was excreted in the form of conjugates and two hydroxy metabolites. A significant amount of radioactivity was excreted in urine. The diversion of bile by cannulation of the bile duct led to a significant decrease of elimination by feces.     

Pharmacokinetics of 14C-etretinate in healthy volunteers and two patients with biliary T-tube drainage

The pharmacokinetic profile of 14C-etretinate, a retinoid that is effective in the treatment of psoriasis, was studied in six healthy male volunteers and two biliary T-tube patients. Following a 100 mg oral dose of 14C-etretinate (20 microcurie), etretinate and its major blood metabolites (etretin, isoetretin) were measured by HPLC and total carbon-14 was measured in blood, bile, urine, and feces by liquid scintillation counting. Etretinate was extensively metabolized in healthy volunteers and in T-tube patients. During the absorption phase, 75 per cent of the total radioactivity in the blood could be accounted for as etretinate, etretin, and isoetretin whereas these compounds accounted for only approximately 12 per cent of the blood radioactivity in T-tube patients over the same time period. The blood concentrations of etretinate, etretin, and isoetretin appeared to be substantially reduced in T-tube patients compared to those in healthy volunteers. A higher proportion of the total drug was excreted in the feces and bile of the T-tube patients (84 per cent) than in the feces of healthy volunteers (62 per cent). The major factor responsible for the observed decrease in etretinate blood concentrations following biliary cannulation appears to be the reduced absorption of etretinate due to the elimination of solubilizing bile salts in the duodenum. Carbon-14 related material was detected in urine and feces for as long as 3 weeks in healthy subjects supporting the previous observation that a long terminal elimination half-life exists for etretinate, even following a single dose of the compound.     

The uptake and subcellular distribution of radio-labelled metabolites of digitoxin in the guinea-pig isolated perfused heart.

1 Comparisons were made of the uptake and inotropic effects of concentrations of 0.1 muM of digitoxin and its cleavage products digitoxigenin-bis-digitoxoside, digitoxigenin-mono-digitoxoside and digitoxigenin in the isolated perfused hearts of guinea-pigs. 2 Digitoxin produced the greatest inotropic responses in this series, while the sequence of cleavage products produced progressively smaller responses. 3 The uptake of digitoxin was significantly higher than that of the three metabolites, and the uptake of metabolites became progressively less with cleavage. The highest binding in each case was found in the microsomal fraction. 4 The uptake of all four digitaloids was reduced when the potassium in the perfusion medium was increased.     

The disposition and metabolism of a hypnotic benzodiazepine, quazepam, in the hamster and mouse

The disposition of 14C-quazepam (7-chloro-(2,2,2-trifluoroethyl) [5-14C]-5-o-fluorophenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-thione), a new benzodiazepine hypnotic, was studied in hamsters and mice after iv and po dosing. In both species, quazepam was rapidly absorbed, as indicated by the plasma Cmax being reached within 1 hr of an oral dose (5 mg/kg). Also, radioactivity is essentially completely absorbed in both species, since the percentage of dose excreted in the urine was not dependent on the route of drug administration. Radioactivity was widely distributed in the tissues of both species; however, it was concentrated (relative to plasma) only in the liver and kidneys. In hamsters, 66-77% of the radioactivity was excreted within 48 hr, and 97% within 7 days of dosing (57% found in urine and 40% in feces after iv; 54% in urine and 43% in feces after po dosing). In mice, 86-88% of the radioactivity was excreted within 24 hr, and 98% within 4 days of dosing (43% in urine and 56% in feces after iv, 37% in urine and 61% in feces after po dosing). In both species, plasma levels of quazepam, measured by GLC, accounted for a very small percentage of plasma radioactivity and the elimination half-life was short (2.4 hr in hamster and 1.2 hr in mice), indicating extensive first pass metabolism for this drug. TLC analysis of plasma and urine extracts from both species showed biotransformation of quazepam involved substitution of oxygen for sulfur, followed by: (a) N-dealkylation, 3-hydroxylation, and conjugation or (b) 3-hydroxylation and conjugation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolism, excretion, and pharmacokinetics of duloxetine in healthy human subjects.

Duloxetine is a potent and balanced dual inhibitor of serotonin and norepinephrine reuptake being investigated for the treatment of depression and urinary incontinence. The disposition of duloxetine was studied in four healthy human subjects after a single 20.2-mg (100.6 microCi) oral dose of [14C]duloxetine in an enteric-coated tablet. The mean total recovery of radioactivity (+/- S.E.M.) after 312 h was 90.5% (+/-0.4%) with 72.0% (+/-1.1%) excreted in the urine. Duloxetine was extensively metabolized to numerous metabolites primarily excreted into the urine in the conjugated form. The major biotransformation pathways for duloxetine involved oxidation of the naphthyl ring at either the 4-, 5-, or 6-positions followed by further oxidation, methylation, and/or conjugation. The major metabolites found in plasma were glucuronide conjugates of the following: 4-hydroxy duloxetine (M6), 6-hydroxy-5-methoxy duloxetine (M10), 4, 6-dihydroxy duloxetine (M9), and a sulfate conjugate of 5-hydroxy-6-methoxy duloxetine (M7). The major metabolites found in plasma were also found in the urine, but the urine contained many additional metabolites. In addition to duloxetine, 4-hydroxy duloxetine (M14) and an unidentified polar metabolite were observed in feces. Following [14C]duloxetine administration, Cmax was reached at a median of 6 h for both duloxetine and total radioactivity. Duloxetine accounted for less than 3% of the circulating radioactivity based on mean area under the curve values. The elimination half-life of total radioactivity (120 h) was substantially longer than that of duloxetine (10.3 h).     

Elimination pathways of [14C]losoxantrone in four cancer patients.

Losoxantrone is an anthrapyrazole derivative in Phase III development in the U.S. for solid tumors, notably breast cancer. To obtain information on the routes of elimination of the drug, a study was conducted in four patients with advanced solid tumors, which involved intravenous administration of 100 microCi of [14C]losoxantrone for a total dose of 50 mg/m(2) during the first course of losoxantrone therapy. Blood, urine, and feces were collected for up to 2 weeks and were analyzed for total radioactivity and parent drug. In addition, feces were profiled for the presence of metabolites. Plasma concentrations of total radioactivity exhibited a temporal pattern similar to the parent drug. Combined recovery of administered total radioactivity from urine and feces was 70% with the majority (87%) of this radioactivity excreted in the feces, presumably via biliary excretion. Feces extracts were profiled for metabolites using a high-performance liquid chromatography method developed to separate synthetic standards of previously identified human urinary metabolites. Only intact losoxantrone was found in the feces. About 9% of the dose was excreted in the urine, primarily during the first 24 h and mostly in the form of parent compound. Collectively, these data indicate that fecal excretion of unmetabolized drug via biliary and/or intestinal excretion is the primary pathway of intravenously administered losoxantrone elimination in cancer patients with refractory solid tumors.     

Evaluation of the excretion and metabolism of the new analgesic agent RWJ-22757 in male and female CR Wistar rats

The excretion and metabolism of (+/-)-trans-3-(2-bromophenyl)octahydroindolizine hydrochloride (RWJ-22757) have been investigated in male and female CR Wistar rats. Radiolabeled [14C] RWJ-22757 was administered orally to each of the rats as a single 60 mg/kg suspension dose. Plasma (0-48 h), urine (0-168 h) and fecal (0-168 h) samples were collected and analyzed. There were no significant gender differences observed in the data. The estimated elimination half-life of the total radioactivity from plasma was 19 h while the estimated elimination half-life of RWJ-22757 was 15 h. Recoveries of total radioactivity in urine and feces were 58.4+/-5.8 and 42.4+/-6.3%, respectively. RWJ-22757 and a total of 11 metabolites were isolated in rat plasma, urine, and fecal extracts. The structures of four of these metabolites were tentatively identified. Unchanged RWJ-22757 accounted for < 4% of the dose in plasma and urine and 28% in feces; thus, indicating the drug was extensively metabolized and either not absorbed well or biliary excreted. Identified metabolites accounted for > 80% of the total radioactivity contained in the samples. The following pathways were used to describe the formation of the metabolites identified in rats: octahydroindolizine ring oxidation, phenyl hydroxylation, octahydroindolizine ring oxidation followed by ring opening to a carboxylic acid function and octahydroindolizine ring oxidation followed by ring opening and N-methylation.     

Isolation and identification of metabolites of 2-ethylhexyl diphenyl phosphate in rats

The metabolic fate of 2-ethylhexyl diphenyl phosphate (EHDPP) was studied in male rats. Orally administered ¹⁴C-EHDPP was rapidly absorbed and about 80% of the radioactivity was excreted in the urine and feces in the first 24 h. By 7 days, 48% and 52% of the radioactivity was recovered in urine and feces, respectively. Since biliary excretion was low (6% for 2 days), urine seems to be the major excretion route of EHDPP. Radioactivity was widely distributed in all tissues examined. At 2 h, the concentration was relatively high in blood, liver kidney and adipose tissue. The elimination of radioactivity from adipose tissue and liver was somewhat delayed, but almost all the radioactivity was eliminated by 7 days. The major metabolites in the urine were diphenyl phosphate (DPP) and phenol. p-Hydroxyphenyl phenyl phosphate (OH-DPP) and monophenyl phosphate (MPP) were also identified as minor metabolites.     

Metabolism and disposition of the flame retardant tris(2,3-dibromopropyl)phosphate in the rat

The metabolism and disposition of the flame retardant, tris(2,3-dibromopropyl)phosphate (Tris-BP), were studied after po and iv administration of the 14C-labeled compound to the male rat. Tris-BP was readily absorbed from the gastrointestinal tract and rapidly distributed throughout the body. The distribution and excretion of Tris-BP derived radioactivity were similar after either po or iv administration. The only effects of route of administration on tissue distribution were slightly higher concentrations in liver after po administration and in lung after iv administration. The initial elimination of Tris-BP derived radioactivity in urine, feces, and as CO2 accounted for approximately 50% of the dose in 24 hr. An analysis of Tris-BP derived radioactivity remaining in the tissues one day after administration indicated that most of the radioactivity in all tissues was in the form of various metabolites rather than the parent compound. The terminal clearance of Tris-BP derived radioactivity from most of the tissues studied was best described by a single component exponential decay with a half-life of approximately 2.5 days. Clearance from liver and kidney was somewhat slower having a half-life of approximately 3.8 days. Approximately 33% of the radioactivity excreted in urine and approximately 50% of the radioactivity excreted in bile were identified by cochromatography with synthesized standards on high performance liquid chromatography (HPLC). Six metabolites and a trace of the parent compound were identified in urine and bile by this method. The six metabolites products of dealkylation and dehydrobromination of the parent compound. The metabolites of Tris-BP isolated from urine and bile were also formed in vitro by NADPH-dependent microsomal enzymes from rat liver. The soluble enzymes from liver metabolized Tris-BP to at least three unidentified polar metabolites.     

Mass balance study of [1?C]eribulin in patients with advanced solid tumors

This mass balance study investigated the metabolism and excretion of eribulin, a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, in patients with advanced solid tumors. A single approximately 2 mg (approximately 80 μCi) dose of [1?C]eribulin acetate was administered as a 2 to 5 min bolus injection to six patients on day 1. Blood, urine, and fecal samples were collected at specified time points on days 1 to 8 or until sample radioactivity was ≤1% of the administered dose. Mean plasma eribulin exposure (627 ng · h/ml) was comparable with that of total radioactivity (568 ng Eq · h/ml). Time-matched concentration ratios of eribulin to total radioactivity approached unity in blood and plasma, indicating that unchanged parent compound constituted almost all of the eribulin-derived radioactivity. Only minor metabolites were detected in plasma samples up to 60 min postdose, pooled across patients, each metabolite representing ≤0.6% of eribulin. Elimination half-lives for eribulin (45.6 h) and total radioactivity (42.3 h) were comparable. Eribulin-derived radioactivity excreted in feces was 81.5%, and that of unchanged eribulin was 61.9%. Renal clearance (0.301 l/h) was a minor component of total eribulin clearance (3.93 l/h). Eribulin-derived radioactivity excreted in urine (8.9%) was comparable with that of unchanged eribulin (8.1%), indicating minimal excretion of metabolite(s) in urine. Total recovery of the radioactive dose was 90.4% in urine and feces. Overall, no major metabolites of eribulin were detected in plasma. Eribulin is eliminated primarily unchanged in feces, whereas urine constitutes a minor route of elimination.     

Plasma concentration, uptake by liver, and biliary excretion of tritiated cardiac glycosides in the isolated perfused guinea-pig liver

1. Investigations were carried out on isolated perfused guinea-pig livers. Different doses of tritiated ouabain, digoxin, and digitoxin were added to the perfusion medium and the subsequent plasma elimination, hepatic uptake, and biliary excretion quantitatively measured. After the perfusion, extracts of liver, bile and plasma were subjected to thin layer chromatography in order to detect the radioactively labelled glycosides and their metabolites.

2. The ouabain concentration in the plasma approached the equilibrium stage within 45 minutes. At this time 40% of the administered dose had been taken up by the liver, and no further elimination occurred. The elimination curve for ouabain followed a simple exponential function. After 1 h the tissue medium (T/M) ratio was approximately 3. In bile hardly any radioactivity could be detected. Ouabain was therefore not excreted by the liver.

3. Up to 80% of the digitoxin was eliminated from the plasma within 4 hours. The elimination of radioactive material for the dose range studied could be described by a hyperbolic function. The T/M ratio in the liver varied with time. At the beginning it was as high as 10 and after 4 h reduced to approximately 3. After 45-60 min the concentration of radioactive material in the bile was 500 times as high as that in the plasma. Almost 70% of the administered radioactivity was excreted with the bile within 4 hours. At the end of the perfusion almost all the identifiable substances in plasma and bile were polar metabolites, as shown by thin layer radiochromatography.

4. Digoxin behaved similarly to digitoxin.

5. The findings led to the following hypothesis: uptake of cardiac glycosides into the liver cells occurs by a passive diffusion process and is related to their lipid solubility. On the other hand excretion in the bile occurs in general if polar metabolites are formed in the liver cells.

     

The metabolic disposition of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-cyanopyridine in rats, dogs, and humans

Studies of the metabolic disposition of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-[14C]cyanopyridine (I) have been performed in humans, dogs, and spontaneously hypertensive rats. After an iv injection of I (5 mg/kg), a substantial fraction of the radioactivity was excreted in the feces of rats (32%) and dogs (31%). After oral administration of I (5 mg/kg) the urinary recoveries of radioactivity for rat and dog were 19% and 53%, respectively, and represented a minimum value for absorption because of biliary excretion of radioactivity. In man, bililary excretion of I appeared to be of minor significance because four male subjects, after receiving 6 mg of I p.o., excreted 76% and 9% of the dose of radioactivity in the urine and feces, respectively. Unchanged I represented 58% of the radioactivity excreted in human urine. The half-life for renal elimination of I was determined to be 4.0 +/- 0.9 /hr. In contrast, unchanged I represented 7% and 1% of excreted radioactivity in rat and dog urine, respectively. A metabolite of I common to man, dog, and rat was identified as 5-hydroxy-I, which represented approximately 5% of the excreted radioactivity in all species. Minor metabolites of I in which the pyridine nucleus had undergone additional hydroxylation were present in dog urine along with an oxyacetic acid metabolite, also bearing a hydroxylated pyridine nucleus.     

The disposition and metabolic fate of 14C-cibenzoline in man

The disposition and metabolic fate of cibenzoline (CBZ) following single oral 153-mg doses of 14C-CBZ succinate were studied in five healthy adult males. The mean maximum plasma radioactivity of 386 ng eq/ml occurred at 2.4 hr after administration. The mean half-life, determined from the 14C plasma concentration and urinary excretion rate data, was 13.1 and 14.8 hr, respectively. The mean maximum CBZ concentration was 196 ng/ml at 1.2 hr post-dose. The mean half-life, determined from the plasma concentration and urinary excretion rate data, was 7.2 and 7.3 hr, respectively. The mean total clearance of radioactivity and CBZ was 300 ml/min and 1224 ml/min, respectively, due to elimination via both renal and nonrenal pathways. The only unconjugated metabolite in the plasma was 4,5-dehydrocibenzoline which, together with other unidentified metabolites, is presumed responsible for the longer observed half-life for total radioactivity. Approximately 75% of the dose was recovered in the urine in the first 24 hr after dosing, 80% of which was present at CBZ and known metabolites. After 6 days, a mean of 85.7% of the dose was excreted in urine and 13.2% in feces. The predominant excreted compound was CBZ (55.7% of the dose) in the 0-72 hr urine. Although several metabolites were identified in urine samples, none were found in substantial amounts relative to the parent drug. Two of these substances showed slight antiarrhythmic activity, whereas the 4,5-dehydro metabolite, representing approximately 4% of radioactivity in urine, was inactive.     

Absorption, metabolism, and excretion of [14C]imidafenacin, a new compound for treatment of overactive bladder, after oral administration to healthy male subjects.

The absorption, metabolism, and excretion of imidafenacin [KRP-197/ONO-8025, 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide], a new antimuscarinic drug developed for treatment of overactive bladder, were assessed in six healthy male subjects after a single oral administration of 0.25 mg of [(14)C]imidafenacin (approximately 46 microCi). The highest radioactivity in the plasma was observed at 1.5 h after administration. The apparent terminal elimination half-life of the total radioactivity was 72 h. Approximately 65.6 and 29.4% of the administered radioactivity were recovered in the urine and feces, respectively, within 192 h after administration. The metabolite profiling by high-performance liquid chromatography-radiodetector and liquid chromatography/tandem mass spectrometry demonstrated that the main component of radioactivity was unchanged imidafenacin in the 2-h plasma. The N-glucuronide conjugate (M-9) was found as the major metabolite and the oxidized form of the 2-methylimidazole moiety (M-2) and the ring-cleavage form (M-4) were detected as the minor metabolites in the 2-h plasma, but M-4 was found to be the main component in the 12-h plasma. Unchanged imidafenacin, M-9, M-2, and other oxidized metabolites were excreted in the urine, but the unchanged imidafenacin and M-9 were not found in the feces. Two unique metabolites were found in the urine and feces, which were identified as the interchangeable cis- and trans-isomers of 4,5-dihydrodiol forms of the 2-methylimidazole moiety. These findings indicate that imidafenacin is rapidly and well absorbed (at least 65% of dose recovered in urine) after oral administration, circulates in human plasma as the unchanged form, its glucuronide, and other metabolites, and is then excreted in urine and feces as the oxidized metabolites of 2-methylimidazole moiety.     

Disposition and biotransformation of the antiretroviral drug nevirapine in humans.

The pharmacokinetics and biotransformation of the antiretroviral agent nevirapine (NVP) after autoinduction were characterized in eight healthy male volunteers. Subjects received 200-mg NVP tablets once daily for 2 weeks, followed by 200 mg twice daily for 2 weeks. Then they received a single oral dose (solution) of 50 mg containing 100 microCi of [(14)C]NVP. Biological fluids were analyzed for total radioactivity, parent compound (HPLC/UV), and metabolites (electrospray liquid chromatography/mass spectroscopy and liquid chromatography/tandem mass spectroscopy). Mean recovery of radioactivity was 91.4%, with 81.3% excreted in urine and 10.1% recovered in the feces over a period of 10 days. Circulating radioactivity was evenly distributed between whole blood and plasma. At maximum plasma concentration, parent compound accounted for approximately 75% of the circulating radioactivity. Mean plasma elimination half-lives for total radioactivity and NVP were 21.3 and 20.0 h, respectively. Several metabolites were identified in urine including 2-hydroxynevirapine glucuronide (18.6%), 3-hydroxynevirapine glucuronide (25.7%), 12-hydroxynevirapine glucuronide (23.7%), 8-hydroxynevirapine glucuronide (1.3%), 3-hydroxynevirapine (1.2%), 12-hydroxynevirapine (0.6%), and 4-carboxynevirapine (2.4%). Greater than 80% of the radioactivity in urine was made up of glucuronidated conjugates of hydroxylated metabolites of NVP. Thus, cytochrome P-450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of NVP biotransformation and elimination in humans. Only a small fraction of the dose (2.7%) was excreted in urine as parent compound.     

Absorption and mass balance of piperonyl butoxide following an 8-h dermal exposure in human volunteers.

Dermal absorption, metabolism and excretion of piperonyl butoxide (PBO) was studied using 14C-PBO either by itself as a 3% (w/w) solution in isopropyl alcohol or as a 4% (w/w) solution in an aqueous end-use formulation. Each of these two formulations were tested on four young, healthy male volunteers, using a single topical application on the ventral forearm under non-occlusive conditions for an 8-h period. The application sites were thoroughly cleaned with cotton swabs moistened with isopropyl alcohol, then rinsed with isopropyl alcohol. Blood from the ipsilateral and contralateral arms, urine and feces were collected at selected intervals during the 8-h application and through a 120-h post-application period. The application area was also tape-stripped to determine if any of the test material accumulated in the stratum corneum. These samples provided data which permitted insight into the kinetics of penetration and elimination processes of PBO. The absorption of PBO either by itself or formulated was very poor, as demonstrated by the radioactivity excreted in the urine, and radioactivity in the ipsilateral plasma. When dosed by itself, approximately 1.78% of the dose was excreted in the urine. In contrast, only 0.47% of the formulated PBO was excreted in the urine. Trace radioactivity was detected in the feces from both formulations. The absorbed radioactivity was rapidly eliminated in the urine. There was no evidence of accumulation of PBO in the skin as evidenced by low amounts of radioactivity in the tape-strippings. The majority of the applied radioactivity was recovered from the skin surface. Total recovery of the applied radioactivity was 100.86 and 104.22% for PBO and the formulated product respectively. Absorbed PBO was completely metabolized to at least three major metabolites prior to its excretion in the urine. The three metabolites represented over 70% of the excreted radioactivity for PBO. The HPLC retention times for these metabolites are different than that seen in rats. The structures of these metabolites have not been elucidated.     

Absorption, distribution, metabolism and excretion of cizolirtine, a new analgesic compound, in rat and dog.

1. The pharmacokinetics of cizolirtine citrate, a new analgesic compound, were studied in the rat and dog following single oral and intravenous doses. 2. Absorption of radioactivity was fast and complete regardless of the species, and no dose and food-related differences were found. However, the elimination half-life of unchanged cizolirtine was shorter in rat than in dog. 3. Tissue distribution of total radioactivity in rat differed widely and a high affinity for liver, kidney, gastrointestinal and pigmented tissues was observed. In blood and almost all tissues the highest concentrations were reached at 20 min; beyond that time the decline of radioactivity in most tissues was parallel to that in blood. 4. The percentage of radioactivity excreted in the rat was 68% in urine and 21% in faeces, the latter being apparently due to drug enterohepatic circulation. In the dog, 92 and 4% of the radioactivity was found in urine and faeces respectively. The contribution of renal excretion to cizolirtine elimination was <5% in rat and 20% in dog. Twelve metabolites were detected in rat and six in the dog by radio-hplc analysis of urine.