In vitro metabolism of quazepam in human liver and intestine and assessment of drug interactions

The study was carried out to identify and characterize kinetically the cytochrome P450 (CYP) enzymes responsible for the major metabolite formation of quazepam. In in vitro studies using human liver and intestinal microsomes and cDNA-expressed human CYP and FMO isoenzymes, quazepam was rapidly metabolized mainly by CYP3A4 and to a minor extent by CYP2C9, CYP2C19 and FMO1 to 2-oxoquazepam (OQ), which was then further biotransformed to N-desalkyl-2-oxoquazepam (DOQ) and to 3-hydroxy-2-oxoquazepam (HOQ) mainly by CYP3A4 and CYP2C9. CYP3A4 is the enzyme predominantly responsible for all the metabolic pathways of quazepam. Itraconazole inhibited the formation of OQ from quazepam, HOQ from OQ and DOQ from OQ in human liver microsomes with Ki values of 8.40, 0.08 and 0.39 microM, respectively. However, the Ki for OQ formation was greater than the peak plasma itraconazole concentration following a clinically relevant 200-mg oral dose to healthy volunteers. In addition, CYP2C9 and CYP2C19 inhibitors failed to inhibit OQ formation from quazepam. In conclusion, clinically relevant drug interaction with CYP inhibitors seem unlikely for the major metabolic pathway of quazepam to OQ.     

Interaction study between fluvoxamine and quazepam

It has been reported that fluvoxamine, an inhibitor of various cytochrome P450 enzymes, markedly inhibits the metabolism of several drugs. The purpose of the present study was to examine a possible interaction between fluvoxamine and quazepam. Twelve healthy male volunteers received fluvoxamine 50 mg/day or placebo for 14 days in a double-blind randomized crossover manner, and on the 4th day they received a single oral 20-mg dose of quazepam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 240 hours after quazepam dosing. Plasma concentrations of quazepam and its active metabolites 2-oxoquazepam (OQ) and N-desalkyl-2-oxoquazepam (DOQ) were measured by high-performance liquid chromatography (HPLC). Fluvoxamine did not change plasma concentrations of quazepam but significantly decreased those of OQ from 6 to 12 hours and those of DOQ from 3 to 48 hours. The AUC ratio of OQ to quazepam was significantly lower in the fluvoxamine phase. Fluvoxamine did not affect psychomotor function at most of the time points. The present study suggests that fluvoxamine slightly inhibits the metabolism of quazepam to OQ, but this interaction appears to have minimal clinical significance.     

In vitro metabolism of quazepam in human liver and intestine and assessment of drug interactions

1. The study was carried out to identify and characterize kinetically the cytochrome P450 (CYP) enzymes responsible for the major metabolite formation of quazepam.

2. In in vitro studies using human liver and intestinal microsomes and cDNA-expressed human CYP and FMO isoenzymes, quazepam was rapidly metabolized mainly by CYP3A4 and to a minor extent by CYP2C9, CYP2C19 and FMO1 to 2-oxoquazepam (OQ), which was then further biotransformed to N-desalkyl-2-oxoquazepam (DOQ) and to 3-hydroxy-2-oxoquazepam (HOQ) mainly by CYP3A4 and CYP2C9. CYP3A4 is the enzyme predominantly responsible for all the metabolic pathways of quazepam.

3. Itraconazole inhibited the formation of OQ from quazepam, HOQ from OQ and DOQ from OQ in human liver microsomes with K_i values of 8.40, 0.08 and 0.39?μM, respectively. However, the K_i for OQ formation was greater than the peak plasma itraconazole concentration following a clinically relevant 200-mg oral dose to healthy volunteers. In addition, CYP2C9 and CYP2C19 inhibitors failed to inhibit OQ formation from quazepam.

4. In conclusion, clinically relevant drug interaction with CYP inhibitors seem unlikely for the major metabolic pathway of quazepam to OQ.     

Placental transfer of quazepam in mice

The disposition of 14C-quazepam following a single 5-mg/kg po dose was studied at the postembryonic period (day 12 of pregnancy) and near-term (day 18 of pregnancy). In both 12- and 18-day pregnant mice, radioactivity from the quazepam dose was widely distributed in the maternal tissues, with the highest levels in the liver and kidneys. At the time points analyzed (1, 5, and 24 hr post-dose), radioactivity levels in the fetus were consistently 44% of the maternal plasma levels in 12-day pregnant mice. In 18-day pregnant mice, fetal radioactivity levels at these time points were consistently equal to or slightly greater than maternal plasma levels. This indicates that radioactivity was taken up and eliminated from fetal tissues at rates that were reasonably similar to those in corresponding maternal tissues. No accumulation of radioactivity was observed in the fetus or in maternal tissues in either the 12-day or the 18-day pregnant mice. In 18-day pregnant mice, concentrations of quazepam and its metabolites were measured either by gas-liquid chromatography or thin layer radiochromatography. In the maternal plasma, concentrations of quazepam, its first-formed metabolite, 2-oxoquazepam, and 3-hydroxy-2-oxoquazepam were relatively low at all time points; levels of N-desalkyl-2-oxoquazepam and 3-hydroxy-N-desalkyl-2-oxoquazepam (HDOQ) were much higher. Fetal levels of unchanged drug and metabolites were generally less than or equal to maternal plasma levels, except for HDOQ levels, which were higher in the fetus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Liquid Chromatographic Assay and Pharmacokinetics of Quazepam and Its Metabolites Following Sublingual Administration of Quazepam

A reverse-phase liquid chromatographic method is described for simultaneous quantification of quazepam, and two of its metabolites, 2-oxoquazepam and N-desalkyl-2-oxoquazepam. The method uses a solid-phase extraction procedure to prepare plasma samples. After extraction, the methanolic extract is evaporated; the residue is then reconstituted in a small volume of mobile phase and chromatographed. The total chromatography time for a single sample is about 20 min. A sensitivity of 1 ng/ml for quazepam and its metabolites is attained when 1 ml of plasma is extracted. Analytical recovery of quazepam and its metabolites added to plasma ranged from 87 to 96%. The maximum within-day and day-to-day coefficients of variation for each compound at concentrations of 20 and 60 ng/ml were 7.6 and 11.2%, respectively. The method was applied to sublingual pharmacokinetic studies of quazepam in healthy volunteers.     

Single oral dose pharmacokinetics of quazepam is influenced by CYP2C19 activity

The effects of cytochrome P450 (CYP)2C19 activity and cigarette smoking on the single oral dose pharmacokinetics of quazepam were studied in 20 healthy Japanese volunteers. Twelve subjects were extensive metabolizers (EMs), and 8 subjects were poor metabolizers (PMs) by CYP2C19 as determined by the PCR-based genotyping. Nine subjects were smokers (>10 cigarettes/d), and 11 subjects were nonsmokers. The subjects received a single oral 20-mg dose of quazepam, and blood samplings and evaluation of psychomotor function were conducted up to 72 hours after dosing. Plasma concentrations of quazepam and its active metabolite 2-oxoquazepam (OQ) were measured by HPLC. There were significant differences between EMs and PMs in the peak plasma concentration (mean +/- SD: 34.5 +/- 16.6 versus 66.2 +/- 19.2 ng/mL, P < 0.01) and total area under the plasma concentration-time curve (490.1 +/- 277.5 vs 812.1 +/- 267.2 ng x h/mL, P < 0.05) of quazepam. The pharmacokinetic parameters of OQ and pharmacodynamic parameters were not different between the 2 groups. Smoking status did not affect the pharmacokinetic parameters of quazepam and OQ or pharmacodynamic parameters. The present study suggests that the single oral dose pharmacokinetics of quazepam are influenced by CYP2C19 activity but not by cigarette smoking.     

Excretion of quazepam into human breast milk

Previous metabolic studies have established that two major metabolites, 2-oxoquazepam and N-desalkyl-2-oxoquazepam, are present in plasma after dosing with quazepam, a new benzodiazepine hypnotic. The excretion of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam into human breast milk was studied in four lactating nonpregnant volunteers. Each volunteer received one 15-mg quazepam tablet following an overnight fast. Nursing of offspring was discontinued after drug administration. Milk and blood samples were collected prior to and at specified times (up to 48 hours) after dosing. Plasma and milk levels of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam were determined by specific GLC methods. The concentrations of the three compounds found in milk appeared to depend on their relative lipophilicities, which were determined by log P values. The mean milk/plasma AUC ratios of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam were 4.19, 2.02, and 0.091, respectively. Levels of quazepam and 2-oxoquazepam declined at about the same rate in plasma and in milk. The total amount of the administered quazepam dose found in the milk as quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam through 48 hours was only 0.11 per cent.     

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.     

Effect of dietary fat content in meals on pharmacokinetics of quazepam

Dietary fat content in meals has been reported to increase the absorption of several drugs proportionately. However, there is no information about the effects of dietary fat in meals on the sedative hypnotic agent quazepam, although limited data suggest that food intake alters quazepam absorption. Therefore, the authors measured and compared pharmacokinetic parameters of quazepam taken in a fasted state and taken 30 minutes after consuming meals containing different amounts of dietary fat. A three-arm randomized crossover study was conducted. Nine healthy male volunteers took a single oral 20-mg dose of quazepam under the following conditions: (1) after fasting overnight for at least 12 hours, (2) 30 minutes after consuming a low-fat meal (two slices of bread and 200 ml of apple juice), or (3) 30 minutes after consuming high-fat meal (two slices of bread with 30 gm of butter and 200 ml of apple juice). Plasma concentrations of quazepam and its metabolite, 2-oxoquazepam, were monitored up to 48 hours after the dosing. In comparison with corresponding plasma values for quazepam taken in a fasting state, the peak concentrations (Cmax) of quazepam taken 30 minutes after consuming a low-fat meal and high-fat meal were 243% (90% confidence interval [CI] = 161%-325%) and 272% (90% CI = 190%-355%), respectively. Area under the plasma concentration-time curve from 0 to 8 hours (AUC(0-8)) and 0 to 48 hours (AUC(0-48)) of quazepam was increased with the low-fat meal by 2-fold (90% CI = 1.5- to 2.7-fold) and 1.4-fold (90% CI = 1.0- to 1.7-fold), respectively, and with the high-fat meal by 2.2-fold (90% CI = 1.3- to 3-fold) and 1.5-fold (90% CI = 0.7- to 2.4-fold), respectively. The pharmacokinetic change in 2-oxoquazepam to the parent compound was similar. Quazepam was well tolerated, with no significant difference in the Stanford Sleepiness Scale between fasted and fed conditions. These findings show that food intake has an evident effect on quazepam absorption, but further studies are needed to clarify a determinant factor of this alteration (2.5-fold for Cmax and 2.1-fold for AUC(0-8), on average). It might not be necessary to do dose adjustment with meal content because quazepam is well tolerated.     

Disposition of 1-naphthol in the channel catfish (Ictalurus punctatus).

The pharmacokinetics, tissue distribution, and metabolism of 1-naphthol were examined in the channel catfish (Ictalurus punctatus). Catfish were administered [1-14C]1-naphthol intravascularly at 1, 5, or 25 mg/kg or orally at 1 mg/kg. Plasma data for 1-naphthol were fitted by a three-compartment pharmacokinetic model. There were dose-related changes in the area under the plasma concentration vs. time curve, apparent volume of distribution, and total body clearance after intravascular dosing. After oral dosing, peak plasma concentrations of 1-naphthol occurred at 1 hr; parent compound made up less than 15% of the total radioactivity, and the bioavailability was 32%. Plasma protein binding was 92% and was independent of concentration. 1-Naphthol and metabolites were rapidly eliminated from the tissues after oral dosing; less than 1% of the administered dose remained at 24 hr. Renal excretion was the primary route of elimination of total 14C. Approximately 60% of the oral dose was excreted in the urine within 48 hr. Parent 1-naphthol made up 1% of the urinary 14C. Major metabolites in the urine were sulfate and glucuronide conjugates, which composed 65 and 28% of the total 14C, respectively. Biliary excretion accounted for 7% of the oral dose. The glucuronide conjugate and an unidentified polar metabolite made up the majority of the biliary 14C. The high capacity of channel catfish for conjugative metabolism of 1-naphthol was demonstrated. The dose dependency of pharmacokinetic values could not be explained by saturable metabolism or plasma protein binding.     

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)     

The disposition and metabolism of [14C]fluconazole in humans.

The disposition and metabolism of 14C-labeled fluconazole (100 microCi) was determined in three healthy male subjects after administration of a single oral capsule containing 50 mg of drug. Blood samples, total voided urine, and feces were collected at intervals after dosing for up to 12 days post-dose. Pharmacokinetic analysis of fluconazole concentrations showed a mean plasma half-life of 24.5 hr. Mean apparent plasma clearance and apparent volume of distribution were 0.23 ml/min/kg and 0.5 liter/kg, respectively. There was no evidence of any significant concentrations of metabolites circulating either in plasma or blood cells. Mean total radioactivity excreted in urine and feces represented 91.0 and 2.3%, respectively, of the administered dose. Mean excretion of unchanged drug in urine represented 80% of the administered dose; thus, only 11% was excreted in urine as metabolites. Only two metabolites were present in detectable quantities, a glucuronide conjugate of unchanged fluconazole and a fluconazole N-oxide, which accounted for 6.5 and 2.0% of urinary radioactivity, respectively. No metabolic cleavage products of fluconazole were detected.     

Disposition of rubratoxin B in the rat

Excretion, tissue concentrations in the kidney and liver, and pharmacokinetic parameters estimated from plasma blood concentrations were determined for rats given a single ip dose of [¹⁴C]rubratoxin B (0.05 mg dissolved in propylene glycol). By 7 days, 80% of the administered radioactivity had been excreted into the urine (41.7%) and feces (38.7%). Urinary excretion was primarily as the parent compound, accounting for 75% of the radioactivity excreted by 7 days. Elimination of radio-activity from the kidneys was monophasic with a half-life of 97.35 hr. Elimination of radioactivity from the liver was biphasic, with a half-life of 13.66 hr for the slow phase. Elimination of rubratoxin B and [¹⁴C]rubratoxin B-derived radioactivity (radioactivity derived from both the parent compound and metabolites) from the plasma was biphasic. The rapid phases of elimination had half-lives of 2.57 and 1.08 hr, and the slow phases had half-lives of 60.80 and 100.46 hr for rubratoxin B and [¹⁴C]rubratoxin B-derived radio-activity respectively. The long plasma half-life of rubratoxin B is suggestive of enterohepatic circulation. The concentration of radioactivity was greatest at 1 hr in the liver and 2 hr in the plasma. Except for the first few hours following injection, the concentration of radioactivity in the liver never exceeded significantly that in the plasma, suggesting a passive absorption process. No glucuronide or sulfate conjugates were detected in the plasma or urine.     

Studies on the metabolism of meptazinol,a new analgesic drug.

1 The absorption, metabolism and excretion of the new analgesic meptazinol has been studied in male volunteers following oral and intravenous administration of a mixture of the [1-14C] and [7-3H] labelled compound. 2 After oral dosage, absorption from the gastrointestinal tract was rapid as evidenced by the early attainment of peak plasma radioactivity levels and near complete as shown by only small amounts of radioactivity recovered in the faeces. 3 Although the absorption of the drug was good, the systemic bioavailability was relatively low. Plasma levels of the unchanged drug remained below the limit of detection (20 ng/ml) after an oral dose of 200 mg. However, after intravenous administration of only 20 mg the peak plasma level was approximately 58 ng/ml. Subsequent elimination was rapid and proceeded in an apparently mono exponential manner with a half-life of approximately 2 hours. 4 Excretion of radioactivity was rapid irrespective of the dosage route and took place chiefly via the urine. Over 60% of the administered radioactivity was recovered in the 0-24 h urine collection. Less than 10% of the administered dose was excreted in the faeces. 5 Less than 5% of the drugs was excreted unchanged. The major metabolite appeared to be the glucuronide conjugate of the parent drug. No evidence was found for N-demethylation of the compound. A minor metabolite of the drug which accounted for approximately 7% of the recovered radioactivity has been tentatively identified as 6-ethyl - 6 - (3-hydroxyphenyl) - 1 - methyl-hexahydroazepin - (2H)-2-ONE.     

Effects of itraconazole on the plasma kinetics of quazepam and its two active metabolites after a single oral dose of the drug

The effects of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4, on the plasma kinetics of quazepam and its two active metabolites after a single oral dose of the drug were studied. Ten healthy male volunteers received itraconazole 100 mg/d or placebo for 14 days in a double-blind randomized crossover manner, and on the fourth day of the treatment they received a single oral 20-mg dose of quazepam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 240 h after quazepam dosing. Itraconazole treatment did not change the plasma kinetics of quazepam but significantly decreased the peak plasma concentration and area under the plasma concentration-time curve of 2-oxoquazepam and N-desalkyl-2-oxoquazepam. Itraconazole treatment did not affect either of the psychomotor function parameters. The present study thus suggests that CYP 3A4 is partly involved in the metabolism of quazepam.     

Pharmacokinetics of primaquine in man: identification of the carboxylic acid derivative as a major plasma metabolite

A method is described for the simultaneous determination of the carboxylic acid and N-acetyl-derivatives of primaquine, in plasma and urine. After oral administration of 45 mg primaquine, to five healthy volunteers, absorption was rapid, with peak primaquine levels of 153.3 +/- 23.5 ng/ml at 3 +/- 1 h, followed by an elimination half-life of 7.1 +/- 1.6 h, systemic clearance of 21.1 +/- 7.1 l/h, volume of distribution of 205 +/- 371 and cumulative urinary excretion of 1.3 +/- 0.9% of the dose. Primaquine underwent rapid conversion to the carboxylic acid metabolite of primaquine, which achieved peak levels of 1427 +/- 307 ng/ml at 7 +/- 4 h. Levels of this metabolite were sustained in excess of 1000 ng/ml for the 24 h study period, and no carboxyprimaquine was recovered in urine. N-acetyl primaquine was not detected in plasma or urine. Following [14C]-primaquine administration to one subject, plasma radioactivity levels rapidly exceeded primaquine concentrations. Plasma radioactivity was accounted for mainly as carboxyprimaquine . Though 64% of the dose was recovered over 143 h, as [14C]-radioactivity in urine, only 3.6% was due to primaquine. As neither carboxyprimaquine nor N- acetylprimaquine were detected in urine, the remaining radioactivity was due to unidentified metabolites.     

Systemic availability and pharmacokinetics of thymol in humans

Essential oil compounds such as found in thyme extract are established for the therapy of chronic and acute bronchitis. Various pharmacodynamic activities for thyme extract and the essential thyme oil, respectively, have been demonstrated in vitro, but availability of these compounds in the respective target organs has not been proven. Thus, investigation of absorption, distribution, metabolism, and excretion are necessary to provide the link between in vitro effects and in vivo studies. To determine the systemic availability and the pharmacokinetics of thymol after oral application to humans, a clinical trial was carried out in 12 healthy volunteers. Each subject received a single dose of a Bronchipret TP tablet, which is equivalent to 1.08 mg thymol. No thymol could be detected in plasma or urine. However, the metabolites thymol sulfate and thymol glucuronide were found in urine and identified by LC-MS/MS. Plasma and urine samples were analyzed after enzymatic hydrolysis of the metabolites by headspace solid-phase microextraction prior to GC analysis and flame ionization detection. Thymol sulfate, but not thymol glucuronide, was detectable in plasma. Peak plasma concentrations were 93.1+/-24.5 ng ml(-1) and were reached after 2.0+/-0.8 hours. The mean terminal elimination half-life was 10.2 hours. Thymol sulfate was detectable up to 41 hours after administration. Urinary excretion could be followed over 24 hours. The amount of both thymol sulfate and glucuronide excreted in 24-hour urine was 16.2%+/-4.5% of the dose.     

High-pressure liquid chromatographic determination of ranitidine, a new H2-receptor antagonist, in plasma and urine

An assay is described for the determination of a new H2-receptor antagonist, ranitidine, and its desmethyl metabolite in human plasma and urine. Alkalinized plasma or urine was extracted with methylene chloride, the organic phase was evaporated, and the reconstituted residue was analyzed by high-pressure liquid chromatography using a reversed-phase column. Two other identified metabolites of ranitidine, the S-oxide and N-oxide, were separated chromtographically from both ranitidine and the desmethyl metabolite. However, these metabolites could not be quantitative due to poor analytical recovery and interference from endogenous components. The sensitivity limits were 5 ng/ml for ranitidine and 15 ng/ml for desmethylranitidine. Plasma samples from two volunteers who were given oral ranitidine (0.1, 0.2, and 0.4 mg/kg) at 1-week intervals were assayed. Peak levels of 30--130 ng/ml were achieved between 40 and 120 min after dosage, followed by an elimination half-life of 2.9-3.9 hr. Plasma levels of ranitidine were still detectable at 8 hr but were below the sensitivity of the assay by 24 hr. Plasma levels of the desmethyl metabolite were seldom above the threshold sensitivity of the assay. Urinary excretion of unmetabolized ranitidine accounted for 77% of the administered dose, whereas only 4% appeared as desmethylranitidine.     

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.     

Pharmacokinetics, metabolism, and routes of excretion of intravenous irofulven in patients with advanced solid tumors.

Irofulven is currently in Phase 2 clinical trials against a wide variety of solid tumors and has demonstrated activity in ovarian, prostate, gastrointestinal, and non-small cell lung cancer. The objectives of this study were to determine its pharmacokinetics and route of excretion and to characterize its metabolites in human plasma and urine samples after a 30-min i.v. infusion at a dose of 0.55 mg/kg in patients with advanced solid tumors. Three patients were administered i.v. 100 microCi of [14C]irofulven over a 30-min infusion on day 1 of cycle 1. Serial blood and plasma samples were drawn at 0 (before irofulven infusion) and up to 144 h after the start of infusion. Urine and fecal samples were collected for up to 144 h after the start of infusion. The mean urinary and fecal excretion of radioactivity up to 144 h were 71.2 and 2.9%, respectively, indicating renal excretion was the major route of elimination of [14C]irofulven. The C(max), AUC(0-infinity), and terminal half-life values for total radioactivity were 1130 ng-Eq/ml, 24,400 ng-Eq . h/ml, and 116.5 h, respectively, and the corresponding values for irofulven were 82.7 ng/ml, 65.5 ng . h/ml, and 0.3 h, respectively, suggesting that the total radioactivity in human plasma was a result of the metabolites. Twelve metabolites of irofulven were detected in human urine and plasma by electrospray ionization/tandem mass spectrometry. Among these metabolites, the cyclopropane ring-opened metabolite (M2) of irofulven was found, and seven others were proposed as glucuronide and glutathione conjugates.