EMIT-st screening for drugs of abuse: methaqualone

The Emit-st (single test) drug detection system was determined, for methaqualone and several of its metabolites, to be reliable and simple to perform. Its sensitivity was 0.3 micrograms/mL for methaqualone and 0.4 micrograms/mL for the only methaqualolne metabolite (4-hydroxymethaqualone) known to be excreted unconjugated. This assay also detects mecloqualone, a Schedule I drug marketed in Europe and South Africa.     

The disposition and pharmacokinetics of ketoconazole in the rat

The disposition, biliary excretion, and pharmacokinetics of ketoconazole in Sprague-Dawley rats were determined after intravenous administration. Greater than 80% of the radioactivity after a 5 mg/kg iv dose of 3H-ketoconazole was excreted in the feces. Urinary excretion was essentially complete after 48 hr; however, fecal excretion was prolonged over a 7-day period. Biliary excretion of radioactivity averaged 54.3 +/- 18.0% of the dose over a 7.5-8-hr period in pentobarbital-anesthesized rats. The possibility of enterohepatic recirculation was examined using a linked rat technique. Less than 2% of the radioactivity was found in the recipient bile over 9-12 hr. In eight male rats, the plasma pharmacokinetics of ketoconazole, as determined by an HPLC assay with fluorescence detection, were as follows: VD = 655 +/- 91 ml/kg, Cl = 14.4 +/- 5.1 ml/min/kg, and t 1/2 = 35.0 +/- 12.3 min. Three of the rats were given an additional oral dose to determine absolute bioavailability. The time to peak was 30-60 min, and the bioavailability was 35.8 +/- 3.55%. Previous studies have indicated that ketoconazole is well absorbed in rats; therefore, the poor bioavailability is probably due to first pass metabolism. The prolonged fecal excretion of radioactivity from an intravenous dose was probably caused by slow elimination of ketoconazole metabolites.     

Pharmacokinetics of digoxin in the turkey and comparison with other species

Digoxin was administered by bolus intravenous injection to seven broad-breasted white turkey poults at doses of 0.1, 0.15, or 0.2 mg/kg. Plasma digoxin concentrations were measured by a ¹²⁵ I radioimmunoassay at selected times over the subsequent 24 hr. The data were fitted to a two compartment open pharmacokinetic model. Overall mean values for kinetic variables were: distribution halflife, 38.96 min; elimination halflife, 11.03 hr; volume of distribution in the central compartment, 1.54 liters/kg; total body clearance, 5.81 ml/min/kg. Different doses did not appear to have a significant effect on the identifiable pharmacokinetic variables, suggesting that digoxin disposition is dose independent in the turkey. The results obtained in turkeys were compared with data reported for rats, cats, dogs, and humans. The value for total body clearance of digoxin in the turkey was similar to values found in man, dogs, and cats but considerably less than values reported for rats. The value for elimination halflife in turkeys was somewhat less than values reported for infants and dogs; however, it was considerably different than values reported for rats and cats.This work was supported in part by NIH Grant HL 18204 and the Dwan Family Fund.     

Serum concentration and urinary excretion of ethambutol administered alone and in combination with isoniazid in patients of pulmonary tuberculosis

Ethambutol (20 mg/kg) was administered orally to 10 patients of pulmonary tuberculosis for seven consecutive days at 8 a.m. after over night fast. On 7th day serum levels were measured at 2, 4, 6, 8 and 24 hr intervals and urinary excretion was estimated at 2, 4, 6 and 24 hr following ethambutol administration. Simultaneous administration of isoniazid (300 mg, orally) for next seven days to the same patients significantly raised the serum levels of ethambutol at 4, 6 and 8 hr and the cumulative per cent dose excreted was decreased significantly at 4, 6 and 24 hr. The serum levels and urinary elimination was not significantly different at 2 hr.     

Urinary excretion of hydromorphone and metabolites in humans, rats, dogs, guinea pigs, and rabbits.

Hydromorphone was administered as a single dose to humans, rats, dogs, guinea pigs, and rabbits, and timed urinary collections were made. GLC-mass spectrometric and GLC analyses of the samples revealed the presence of the parent compound and both 6-hydroxy epimers as metabolites in the urine of all species. Free or conjugated parent drug predominated, while levels of free or conjugated 6beta-hydroxy metabolite were higher than or equal to those of the 6alpha-form. The time courses of excretion of drug and metabolites were similar for all species, with the major portion being excreted in the first 24 hr. Generally, free and conjugated drug were undetectable in human urine after 8 and 48 hr, respectively.     

Pharmacokinetics of digoxin in normal subjects after intravenous bolus and infusion doses

Normal subjects were given 0.75 mg of intravenous digoxin as a bolus and a 1-hr infusion, Radio-immunoassayed serum concentrations obtained over 48 hr and urinary excretion rates over 6 days were simultaneously fitted to a two- compartment open model by computer nonlinear least-squares regression. Serum concentration data alone were also fitted by this program. There was good agreement in calculated parameters between the two routes of administration in five of eight subjects, but the infusion mode of administration produced less variability in the apparent pharmacokinetic constants. The half-life values obtained from serum concentration data alone (24.2 hr) underestimated the half-lives obtained by the simultaneous fit (44.1 hr). The steady-state volume of distribution of digoxin averaged 590±164 liters (±1 sd).The renal clearance of digoxin (140±41 ml/min/1.73 m ² )was significantly higher than creatinine clearance (101±13 ml/min/ 1.73 m ² ),indicating tubular secretion of the drug. Digoxin body clearances were 188±44 ml/min/ 1.73 m ² ,indicating elimination of 25% of the dose by nonrenal mechanisms. Urinary excretion data are essential for proper pharmacokinetic analysis of digoxin disposition and reveal a slower rate of elimination than that suggested by earlier studies which determined only serum concentrations.Supported in part by Grant 20852 from the National Institutes of General Medical Sciences, National Institutes of Health.     

Biliary excretion of arsenic in rats,rabbits, and dogs

The disappearance of ⁷⁴As from blood and plasma of rats and its excretion into bile was measured for 2 hr after the iv administration of 0.01, 0.46, 1.0, 2.1, and 4.6 mg/kg of arsenic given as the trichloride. Arsenic disappearance from plasma was biphasic; the half-life during the late phase was greater than 2 hr. Even though the arsenic was injected iv, the concentration in the blood increased through the first 2 hr. Arsenic was rapidly excreted into the bile, reaching its highest rate of excretion 6 min after administration, after which it rapidly decreased. This rapid decrease in excretion is due to redistribution of arsenic from the liver to the blood. Arsenic enters bile against an apparent bile/plasma concentration gradient of 630, 8 min after 1 mg/kg of arsenic. At this time the liver/plasma gradient is 17 and the liver/bile gradient is 37. Twenty-five percent of the arsenic administered to bile duct-cannulated rats is excreted into the bile within 2 hr. However, less than 10% of the administered dose is excreted into the feces of intact rats over a 7-day period. In the rabbit and dog, arsenic is excreted into the bile at a much slower rate. These data demonstrate that arsenic is excreted into the bile, and this occurs against a large bile/plasma concentration gradient in rats, suggesting excretion by an active transport mechanism. However, the overall importance of bile as a route of elimination for arsenic is minimized due to enterohepatic circulation and species variations in its biliary excretion rate.     

Pharmacokinetic studies on the selectiveβ 1-receptor antagonist metoprolol in man

The pharmacokinetics of ³H-metoprolol, a new selective ₁-receptor antagonist, have been studied in healthy volunteers by following the plasma concentrations and the urinary excretion of the unchanged compound and its total radioactive metabolites after oral and intravenous administration. The compound was rapidly and completely absorbed after oral administration, and about 40% of the dose reached the systemic circulation. The estimated half-life of the absorption process was 10 min. Metoprolol was extensively distributed to extravascular tissues, with the half-life of the distribution phase close to 12 min. About 95% of the dose was excreted in the urine within 72 hr, mainly in metabolized form. The elimination halflife of the compound was close to 3 hr as was also the half-life of the total metabolites after oral administration. After intravenous administration, the elimination half-life of the metabolites was raised to 5 hr, indicating that the route of administra tion might influence the metabolic pathways of the parent compound.     

Excretion Profiles of the Mycotoxin Deoxynivalenol, following Oral and Intravenous Administration to Sheep

Excretion Profiles of the Mycotoxin Deoxynivalenol, followingOral and Intravenous Administration to Sheep. PRELUSKY, D. B.,VEIRA, D. M., TRENHOLM, H. L., AND HARTIN, K. E. (1986). Fundam.Appl. Toxicol. 6, 356–363. The excretion profiles of deoxynivalenol(DON) and metabolites (DON glucuronide conjugate, 3,715-trihydroxytrichothec-9,12-diene-8-one(DOM-1), and DOM-1 glucuronide conjugate) were defined in malesheep following either intravenous (iv) or oral administrationof the toxin at levels of 0.5 and 5.0 mg DON/kg body wt, respectively.After iv dosing, urinary DON levels declined in a biphasic fashionwith an average elimination half-life (terminal phase) of 1.2hr. diminishing to baseline concentrations by 8 hr. Maximumurinary excretion rates for the two major metabolites identified(conjugated DON, conjugated DOM-1) occurred 0.5–1.5 hrafter dosing, exhibiting elimination half-lives of 2.2 and 3.1hr, respectively. Total recovery accounted for only about 66.5%of the dose: 63.0% in the urine (24.1% DON, 21.2% conjugatedDON, 0.5% DOM-1, 17.2% conjugated DOM-1) and 3.5% in bile (madeup almost completely of conjugated DOM-1). The peak biliaryexcretion rate for conjugated DOM-1 was found to occur within1 hr postdosing, which rapidly declined to baseline levels by5 hr. Following oral administration, urinary excretion ratesof the major metabolites (DON, conjugated DON, conjugated DOM-1)reached maximum 6–9 hr post-treatment, and declined exponentiallywith t values of 3.2, 4.0, and 5.0 hr, respectively. Urinaryand biliary recovery of administered DON averaged approximately7.1%: 7.0% in urine (2.1% DON, 3.6% conjugated DON, 0.06% DOM-1,1.2% conjugated DOM-1) and 0.11% in bile (predominately conjugatedDOM-1). Between 54 and 75% of the oral dose was recovered inthe feces. These findings indicate that DON and metabolitesdo not persist in the body following either a single oral orintravenous dose of DON and are rapidly excreted. However, followingiv administration, a portion of the dose (33.5%) remained unaccounted,presumably converted to unidentified metabolites. Based on theseresults it appears that metabolism is the major process of eliminationof DON in sheep.     

Urinary excretion of ecgonine methyl ester, a major metabolite of cocaine in humans

In this study, cocaine, benzoylecgonine, and ecgonine methyl ester excretion in urine was measured after intravenous and intranasal administration of cocaine at 16, 32, 48, and 96 mg doses to healthy cocaine users. Ecgonine methyl ester and cocaine were analyzed by gas chromatography/mass spectrometry. Benzoylecgonine was measured by immunoassay (EMIT) and liquid chromatography. Urinary ecgonine methyl ester accounted for 26 to 60% of the cocaine dose. Ecgonine methyl ester had an elimination halflife of 4.2 hr, compared with 5.1 hr for benzoylecgonine. These results indicate that ecgonine methyl ester accounts for most of the previously unidentified urinary metabolic products of cocaine. The time course of ecgonine methyl ester excretion is such that its detection can substitute for benzoylecgonine detection as a marker of cocaine use.     

Forensic drug testing for opiates, III. Urinary excretion rates of morphine and codeine following codeine administration

The urinary excretion profile of free and conjugated codeine and morphine was determined by GC/MS for four healthy male subjects after intramuscular administration of 60- and 120-mg doses of codeine. Codeine and metabolites were rapidly excreted with the majority of drug appearing in the first 24 h. No dose-related differences in metabolism were observed. The initial ratio of total codeine to total morphine was substantially greater than 1.0 but declined over time. For two of the four subjects, the codeine-morphine ratio declined below 1.0 late in the elimination phase. With a 300-ng/mL cutoff, one subject tested positive on more than one occasion for total morphine and negative for codeine during the terminal elimination phase. The data indicate that urine codeine-morphine ratios are not reliable indices of the type of opiate exposure.     

Pharmacokinetics of o-nitroanisole in Fischer 344 rats

The pharmacokinetics and metabolism of o-nitroanisole (ONA) were studied in male Fischer 344 rats. Three dose levels of [14C]ONA (5.0, 50, or 500 mg/kg) were administered orally to rats and daily excreta were analyzed for 14C. Since the highest dose altered the urinary excretion rate of ONA, a dose of 25 mg/kg was used for subsequent pharmacokinetic studies. Following a single 25 mg/kg iv dose of [14C]ONA, blood, tissues, and excreta were collected at times ranging from 15 min to 7 days. Urinary excretion accounted for 82% of the dose by 24 hr and 86% by 7 days. Fecal excretion was 7.5% in 24 hr and 9.0% by 7 days. Fifteen min after ONA administration, most of the 14C content was found in muscle (20%), skin (10%), adipose tissue (6.8%), and blood (6.5%). All other tissues contained less than 5% of the dose. Within 8 hr, less than 1% of the dose was present in any tissue. The initial elimination t1/2 for 14C in all tissues was 1-2 hr and the terminal t1/2 was approximately 4 days. The elimination of parent ONA from blood followed first order biphasic elimination kinetics (initial t1/2 = 30 min; terminal t1/2 = 2.2 hr). Parent ONA was rapidly eliminated from all other tissues in a monophasic manner (t1/2 = 15 min to 2 hr). Skin and fat demonstrated an uptake phase prior to the elimination of parent. Only 0.5% of the dose was excreted as ONA in the urine. Urinary metabolites of ONA were predominantly conjugated compounds (63% as sulfates; 11% as glucuronides).     

Methaqualone pharmacokinetics after single- and multiple-dose administration in man

Serum levels of methaqualone (MTQ) were determined in eight unfasted subjects following single- and multiple-dose administration of 1×300 mgtablet over a 28-day period. Data were analyzed by a two-compartment open model. Following a fairly rapid absorptive phase (K _a =0.82±0.32 hr^–1),the serum elimination curve was biexponential, consisting of a phase predominantly due to distribution (=0.97±0.55 hr^–1)and a phase predominantly due to elimination (=0.036±0.004 hr^–1).A steady-state MTQ serum concentration profile was observed within the first week. There were no significant changes in the kinetics of absorption, distribution, or elimination over the 28-day period of drug administration. Urinary D-glucaric acid excretion, which increased two-to threefold after the first week of MTQ dosing, returned to normal levels when the drug was discontinued. The significance of the pharmacokinetic parameters in relation to bioavailability and biological disposition of single and multiple dose MTQ administration is discussed.     

Studies on flavonoid metabolism Absorption and metabolism of (+)-catechin in man

Oral administration of (+)-catechin to man results in absorption, rapid metabolism and excretion of the compound largely within 24 hr. Eleven (+)-catechin metabolites are detected in the urine. The major phenolic acid metabolite is m-hydroxyphenylpropionic acid and the major lactone metabolites include δ-(3,4-dihydroxyphenyl)-γ-valerolactone and δ-(3-hydroxyphenyl)-γ-valerolactone. The phenolic compounds in the urine are excreted in both free and conjugated forms, including their glucuronides and to a lesser degree their ethereal sulphates. Absorption of (+)-catechin occurs in the gastrointestinal tract as early as 6 hr after the oral administration of the compound and appears in the urine together with several unidentified metabolites both in the free and conjugated forms. The amount excreted within 24 hr is about 7.5 per cent of the administered dose. The stomach gastric juice do not degrade (+)-catechin in vitro but prolonged contact with the gastric juice causes some polymerisation of the compound. Unchanged (+)-catechin amounts to about 18.6 per cent of the administered dose in the 48 hr faecal collection. In addition, m-hydroxyphenylpropionic acid and one unidentified metabolite are detected in the faeces. The rise in phenolic levels in the blood occurs as early as 6hr after the oral administration of (+)-catechin and parallel to the rise in urinary excretion of phenolic compounds.     

Pharmacokinetic and Metabolic Disposition of p-Chloro-m-xylenol (PCMX) in Dogs

The pharmacokinetic and metabolic profile of p-chloro-m-xylenol (PCMX) was studied in healthy mongrel dogs after intravenous and oral administration of single doses of 200 and 2000 mg of PCMX, respectively. Calculation of pharmacokinetic parameters was based on compartmental and noncompartmental methods. The mean pharmacokinetic parameters of elimination half-life and mean residence time were 1.84 and 1.69 hr, respectively. The apparent volume of distribution at steady state was estimated to be 22.4 liters, and the plasma clearance was 14.6 liters/hr. The bioavailability of PCMX was 21%, indicating low absorption for this drug. PCMX's metabolite data show that a presystemic elimination process (first-pass effect) is also occurring. PCMX plasma concentrations after intravenous administration of 500-, 200-, and 100-mg doses were found to be proportional to the dose given, demonstrating that the pharmacokinetic profile of PCMX is linear over the dose range studied. Biotransformation studies showed that urinary excretion was not the major route for rapid elimination of unchanged PCMX and almost all material excreted in urine was associated with the conjugated species (glucuronides and sulfates). Statistical significant differences were not found (P > 0.05) between the percentages excreted in urine of PCMX and its conjugated metabolites after intravenous and oral administration. The percentages excreted in urine after iv and oral doses of unchanged PCMX were, respectively, 0.45 and 0.37; total conjugates, 46.3 and 43.3; sulfates, 38.1 and 33.2; and glucuronides, 8.2 and 10.2.     

Pharmacokinetics and tissue distribution of 2-fluoro-beta-alanine in rats. Potential relevance to toxicity pattern of 5-fluorouracil.

Clinical pharmacokinetic studies in our laboratory demonstrated that 2-fluoro-beta-alanine (FBAL), the major catabolite of fluorouracil (FUra), has a prolonged elimination with an approximately 150-fold longer half-life than that of the unchanged drug in humans [Heggie et al.: Cancer Res. 47, 2203-2206 (1987)]. Recent studies have suggested that FUra catabolites, such as FBAL, may have a role in neurotoxicity and cardiotoxicity that may occur during FUra chemotherapy [Okada et al.: Acta Neuropathol. 81, 66-73 (1990)]. This study was undertaken to determine the kinetics and tissue distribution of FBAL in rats following iv bolus administration of radiolabeled FBAL. Plasma disappearance curves for FBAL could be described by the sum of three exponentials, with half-lives of 0.26, 12.1, and 8426 min. Radioactivity, consisting mainly of FBAL-bile acid conjugates, was excreted in bile within 30 sec of iv bolus administration of FBAL and continued throughout the experimental period at concentrations 10-100-fold higher than that of the corresponding plasma level. Urinary excretion, consisting mainly of free FBAL, represented the major pathway of elimination of FBAL, with 40% of the administered dose excreted within 24 hr and approximately 70% over 192 hr. Fecal excretion was a minor pathway of elimination of FBAL, with approximately 10% of the administered dose excreted over 192 hr. During the initial 30 min, the highest levels of tissue radioactivity were found in the kidneys, liver, spleen, lungs, and heart. Radioactivity was retained over longer time periods in the enterohepatic circulation, central nervous system, heart, and skeletal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition and metabolic fate of 14C-quazepam in man

The absorption, metabolism, and excretion of quazepam, a new benzodiazepine hypnotic, was investigated in six normal male volunteers after oral administration of 25 mg 14C-quazepam in solution. Quazepam was well absorbed. Plasma radioactivity peaked (324.6 ng quazepam eq/ml) 1.75 hr postdose. Unchanged quazepam reached its maximum plasma level (148 ng/ml) at 1.5 hr with an apparent absorption half-life of 0.4 hr. Major plasma metabolites of quazepam were 2-oxoquazepam (OQ), obtained by replacement of S by O,N-desalkyl-2-oxoquazepam (DOQ), and 3-hydroxy-2-oxoquazepam (HOQ) glucuronide. Both OQ and DOQ are pharmacologically active. Plasma elimination half-lives for quazepam, OQ, DOQ, and radioactivity were 39, 40, 69, and 76 hr, respectively. The respective AUC (120 hr) values were 715, 438, 3323, and 11402 hr X ng/ml. Approximately 54% of the radioactive dose was excreted in the urine (31.3%) and feces (22.7%) over a 5-day period. HOQ glucuronide was the major urinary metabolite of quazepam. Other metabolites present in the urine in relatively large amounts were glucuronides of DOQ and HDOQ.     

Disposition and excretion of intravenous 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) in rats

Polybrominated dibenzodioxins and dibenzofurans are of toxicologic interest due to potential occupational and environmental exposure and because of their structural similarity to the highly toxic chlorinated analogues. The excretion and terminal tissue distribution of [3H]TBDD was studied in male F344 rats for 56 days following single iv doses of .001 or 0.1 mumol/kg. The major tissue depots of radioactivity were liver, adipose tissue, and skin, and tissue distribution was dose-dependent. At 56 days, liver concentrations in the high dose group were disproportionately increased compared to those of the low dose group. Liver:adipose tissue concentration ratios were 0.2 and 2.6 at the low and high doses, respectively. Elimination of radioactivity in the feces, the major route of excretion, and urine was also nonlinear with respect to dose. By Day 56, feces accounted for approximately 50% of the administered dose at the low dose versus 70% at the high dose. Based on fecal excretion, the apparent terminal whole body half-life was estimated to be 18 days for both dose groups. The time-dependent pattern of tissue disposition was characterized at the low dose over a 56-day period. Blood levels of radioactivity declined rapidly with 2% remaining in the blood by 24 hr. Radioactivity levels in the liver peaked by 7 hr and then gradually declined concomitant with a slow accumulation in adipose tissue. The terminal excretion half-life of radioactivity in adipose tissue was estimated to be 60 days. Liver:adipose tissue concentration ratios declined with time. Thus, the overall disposition of TBDD appears similar to that observed for the chlorinated analogue, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The results of these studies are consistent with the hypothesis that TBDD, like TCDD, induces a binding species in the liver which accounts for higher liver:adipose tissue concentration ratios at the high dose. The dose-dependent tissue disposition and excretion kinetics of these compounds suggest important considerations for extrapolations from high to low doses.     

Elimination and excretion of a single dose of the mycotoxin fumonisin B2 in a non-human primate.

The mycotoxin fumonisin B2 (FB2), which can be present at significant levels in maize infected with the fungus Fusarium moniliforme, was dosed both iv and by gavage to vervet monkeys. It was rapidly eliminated from the plasma of vervet monkeys dosed i.v. with 2 mg FB2/kg body mass. The concentration of FB2 in plasma after the iv dose was characterized by an initial distributional phase and a subsequent elimination phase with a mean half-life of 18 min. When two monkeys were dosed by gavage with a single bolus (7.5 mg/kg body mass), only one showed detectable trace levels of FB2 in plasma (25-40 ng/ml over the 3-5 hr period after dosing). This indicates that, like FB1, FB2 has a limited bioavailability. Urinary excretion of FB2 was extremely low, even after i.v. dosing. In total, a mean of 4.1% of the i.v. dose and 0.2% of the gavage dose was recovered in urine over a 7-day period. The predominant route of excretion was via the faeces, mainly as the unmetabolized toxin or as a partially hydrolysed analogue, with the latter accounting for between 6% and 47% of the dose. Limited amounts (maximum of 1.1%) of the fully hydrolysed aminopolyol backbone of FB2 were recovered in faeces.     

Disposition and metabolism of radiolabelled pentachloroanisole in rats and rabbits

Male Sprague-Dawley rats and New Zealand White rabbits were administered ¹⁴C-labelled pentachloroanisole (PCA) in corn oil by gavage as single doses of 25 mg/kg and were then placed in individual metabolism cages for as long as 4 days. Peak blood level of radioactivity occurred 6 hr after administration of the dose to rats and between 3 and 4 hr in rabbits; the blood elimination half-life ranged from 8 to 15 hr in rats and averaged 6 hr in rabbits. Rats excreted an average of 54.2% of the administered radiolabel in the urine and 32.4% in the faeces during the 96 hr following the dose; rabbits excreted an average of 84.2 and 13.1% of the radiolabel in the urine and faeces, respectively, during this time. Examination of the metabolites in the rat showed that 60% of the urinary radioactivity was attributable to tetrachlorohydroquinone (TCH). 3% to free pentachlorophenol (PCP) and 29% to conjugated PCP; faecal metabolites were PCP (85.7%), TCH (4.3%) and polar metabolite(s) (10%). In the rabbit, 58% of the urinary radioactivity was attributable to TCH. 8% to free PCP and 34% to conjugated PCP. Faecal metabolites consisted of PCP and conjugated material.