The metabolism and urinary excretion in man of phentermine,and the influence of N-methyl and p-chloro-substitution*

The urinary excretion of phentermine, mephentermine and chlorphentermine was examined after oral administration of phentermine and chlorphentermine hydrochlorides and mephentermine sulphate to man under normal and acidic conditions of urinary pH. The rate of excretion of both phentermine and mephentermine fluctuated with changes in urine pH, a more acidic pH causing a faster rate of excretion; changes in urine flow rate had only a slight effect. The rate of excretion of chlorphentermine was affected by changes in pH and urinary flow rates. Phentermine and mephentermine were recovered almost quantitatively within 24 h from subjects under acidic urine control; only about 35% chlorphentermine was recovered under similar conditions.     

The influence of diuretics on the excretion and metabolism of doping agents. II. Phentermine

The urinary excretion of phentermine in humans was followed over a period of several days after the oral administration of two formulations. The intake of phentermine in a capsule generally resulted in an excretion peak 4 h after the administration followed by a second peak 12 or 24 h post dosing. The total amount excreted during 72 h varied from 62.7 to 84.8%. Concerning the administration of Ionamine 15, a sustained release formulation, the maximal excretion rate was spread over 3-9 h, while more than 85% of phentermine were excreted after 72 h. The excretion was affected by urinary pH. The intake of acetazolamide shortly after phentermine resulted in a decrease of the phentermine excretion during one day and in one subject in a suppression below the detection limit 4 h post dosing. The administration of furosemide or bumetanide produced only a diluting effect during 2 h.     

The influence of diuretics on the excretion and metabolism of doping agents. III. Etilamfetamine

The urinary excretion of etilamfetamine (ethylamphetamine) and its major metabolite amphetamine in humans was followed over a period of several days after the oral administration of two formulations. The excretion of both substances was affected by urinary pH. Excretion peaks were observed 3-4 h after the ingestion of etilamfetamine in a capsule and the proportion of etilamfetamine excreted during 72 h was 22.2 to 54.4%. Excepting a shift in the peak excretion time to 4-5 h, no meaningful pharmacokinetic differences were found when Apetinil-Depot, a retard formulation, was administered. The intake of acetozolamide shortly after etilamfetamine resulted in a decrease of the etilamfetamine excretion during one day and a suppression below the detection limit for periods varying from 2-7 h post-dosing. Although the etilamfetamine excretion was suppressed from 2 to at least 10 h post-dosing, the action of the diuretic clofenamide on the etilamfetamine excretion is generally not so obvious as that of acetazolamide. The administration of furosemide only reduced the etilamfetamine concentrations by a factor of 4 to 5 during a 2-h period.     

Urinary and biliary metabolites of mephentermine in male Wistar rats

1. Excretion of urinary and biliary radioactivity, and metabolites of [3H]mephentermine (MP), after i.p. or subcutaneous administration of [3H]MP to male Wistar rats, were determined by preparative t.l.c.-liquid scintillation counting. 2. About 45% of the radioactivity administered i.p. was excreted in the 24 h urine. The major urinary metabolite was conjugated p-hydroxymephentermine (p-hydroxy-MP), which accounted for about 18% of the administered radioactivity in the 24 h urine. 3. About 4.2% of the radioactivity administered subcutaneously was excreted in bile during 24 h. The major biliary metabolite was conjugated p-hydroxy-MP, which accounted for about 39% of the radioactivity excreted in the bile in 24 h. 4. Urinary and biliary minor metabolites detected were phentermine (Ph), p-hydroxyphentermine (p-hydroxy-Ph), N-hydroxyphentermine (N-hydroxy-Ph), N-hydroxymephentermine (N-hydroxy-MP) and their conjugates, and conjugated MP. 5. The conjugates were considered to be glucuronides from the inhibitory effect of saccharic acid 1,4-lactone on their hydrolysis with beta-glucuronidase. 6. Biliary excretion rates of conjugated p-hydroxy-Ph and p-hydroxy-MP reached maxima at 3 to 4 h, and non-conjugated metabolites were maximal at 1 to 2 h, after administration. 50% of the biliary metabolites was excreted within 5 h.     

Detection and metabolism of fencamfamine and the influence of acetazolamide on its urinary excretion

A gas-chromatographic (g.l.c.) method with electron-capture (e.c.) detection is described for the simultaneous quantitative determination of nanogram concentrations of 2-ethylamino-3-phenyl-norbornane (Fencamfamine, REACTIVAN®) and its metabolite 2-amino-3-phenylnorbornane in urine. The renal excretion of fencamfamine and its metabolite after oral administration to humans was followed over a period of several days. The excretion of both substances was affected by urinary pH. Excretion peaks were obtained 2–4 h after ingestion and the total amount excreted during 80 h varied from 11.9 to 33.2 per cent. Based on urinary values, the biological half life of fencamfamine was 16 h. The intake of acetazolamide shortly after fencamfamine resulted in a decrease of the fencamfamine excretion and a suppression of the metabolite output during at least 10 h. Acetazolamide did not influence the percentage of the doses excreted during 80 h. No changes occurred in urinary fencamfamine or metabolite concentrations during storage of the urine at — 18° for 6 weeks.     

The influence of diuretics on the excretion and metabolism of doping agents. Part IV--Caffeine

The urinary excretion of caffeine in humans was followed over a period of 36 h after the oral administration of ANIMINE, a formulation containing caffeine-alpha-naphthylacetate. The excretion of caffeine was not as markedly affected by the urinary pH as was found with stimulant amines. Excretion peaks were obtained 1-2 h after the ingestion and the total amount of unchanged caffeine excreted during 12 h varied from 0.57 to 1.51 per cent. The ingestion of the diuretics acetazolamide or furosemide 2 h after caffeine resulted in a urine-flow dependent and consequently increased caffeine excretion during 2-4 h post-diuretic. This increase paralleled the increase in urine volume resulting in no meaningful differences in caffeine concentration compared to normal conditions.     

The effect of diuretics on the faecal excretion of water and electrolytes in horses.

1. The effect on plasma, urinary and faecal electrolytes of frusemide and hydrochlorthiazide was measured in ponies, mean weight 180 kg. 2. The rapid loss in urine of large quantities of sodium had only a small effect on plasma sodium concentration. 3. Faecal sodium excretion was increased substantially after the administration of frusemide. 4. Frusemide increased faecal potassium during the 48 h following administration and faecal water in the 24/48 h period. It also produced a hypopotassaemia. 5. Hydrochlorthiazide increased faecal chloride during the 24 h after administration. 6. Frusemide increased the intestinal transit time of both liquid (polyethylene glycol) and particulate (Cr2O3) markers.     

Metabolism of mephentermine in male guinea pigs and male mice.

1. Urinary metabolites of mephentermine (MP), after i.p. administration of MP to male Hartley guinea pigs and mice, were identified by g.l.c.-electron impact (EI) mass spectrometry. Excretion of urinary radioactivity, and metabolites of 3H-MP, after i.p. administration, were determined by preparative t.l.c.-liquid scintillation counting. 2. About 27% of the radioactivity administered was excreted in the 24 h urine of guinea pigs, and 36% dose was excreted in 5 days. In mice, about 47% of the radioactivity was excreted in the 24 h urine, and 52% in 5 days. 3. Excretion rates of metabolites detected in the 24 h urine of guinea pigs were phentermine (Ph, 7.8%), a conjugate of N-hydroxyphentermine (N-hydroxy-Ph, 3.6%), p-hydroxyphentermine (p-hydroxy-Ph, 1.0%) and its conjugate (2.9%), and other metabolites (conjugates of MP and Ph, N-hydroxymephentermine (N-hydroxy-MP) and its conjugate, p-hydroxymephentermine (p-hydroxy-MP) and its conjugate, and N-hydroxy-Ph; less than 1.0%). The rates of excretion for mice were Ph (11.7%), conjugates of p-hydroxy-MP (3.1%), Ph (2.7%) and p-hydroxy-Ph (1.6%), and N-hydroxy-Ph (1.2%) and other metabolites (conjugates of MP and N-hydroxy-Ph, N-hydroxy-MP and its conjugate, p-hydroxy-Ph, and p-hydroxy-MP; less than 1.0%). 4. These results indicate that MP administered to mice is metabolized mainly to Ph and p-hydroxy-MP by N-demethylation and p-hydroxylation of the parent compound, and in guinea pigs the primary metabolic reaction of MP is N-demethylation producing Ph.(ABSTRACT TRUNCATED AT 250 WORDS)     

Natriuretic effect of barnidipine, a long-acting dihydropyridine calcium channel blocker, in patients with essential hypertension

OBJECTIVE: To evaluate the effect of barnidipine hydrochloride, a long-acting dihydropyridine calcium channel blocker on urinary sodium excretion in patients with essential hypertension. PATIENTS: Twelve patients (2 males, 10 females) with mild to moderate essential hypertension. METHODS: A single-blinded study. After the control (placebo) period, 10 to 15 mg barnidipine hydrochloride was administered for 7 days, followed by a post-treatment (placebo) period. Daily changes in blood pressure, urinary volume, and urinary electrolyte excretions were evaluated. Plasma levels of atrial natriuretic peptide (ANP) and aldosterone were also determined in each period. Daily sodium intake was kept at 120 mEq. RESULTS: Blood pressure decreased from 161 +/- 4/92 +/- 2 mmHg to 146 +/- 4/85 +/- 2 mmHg (p<0.05) after 7-day-treatment with barnidipine. Barnidipine significantly increased urinary sodium excretion; the change was evident on the first day of administration (control period 41 +/- 3 mEq/day, and first day 59 +/- 3 mEq/day, p < 0.05). Drug discontinuation transiently decreased sodium excretion to 35 +/- 3 mEq/day. Cumulative sodium balance after 7-day-treatment reached 47 +/- 19 mEq. Urine volume, potassium excretion, and creatinine excretion did not change during the treatment period. The plasma levels of ANP tended to increase, but those of aldosterone did not change with barnidipine. CONCLUSION: Barnidipine administration for a week decreased the blood pressure and made the sodium balance negative by increasing the urinary sodium excretion in patients with essential hypertension. The natriuretic effect of this drug could contribute at least in part to its antihypertensive effect.     

The absorption of trichloroethylene and its metabolites from the urinary bladder of anesthetized dogs

In order to examine the absorption of trichloroethylene (TRI) and its metabolites from the urinary bladder of dogs, we injected TRI and its metabolites, i.e., chloral hydrate (CH), free trichloroethanol (F-TCE), trichloroacetic acid (TCA) and conjugated trichloroethanol (Conj-TCE), into the urinary bladder of anesthetized dogs, and measured the agents and their respective metabolites in the blood or serum, urine and bile. The percentage of water absorbed from the urinary bladder was 10-20% 2 h after the administration of all substances. The percentage of agents absorbed was 60-70% for the TRI and TCA groups, and 50-60% for the CH, F-TCE and Conj-TCE groups 2 h after administration. The combined urinary and biliary excretion rates of the absorbed materials from the urinary bladder 2 h after administration were 46% for F-TCE, 30% for CH, 6% for Conj-TCE and 0.5-1.0% for TRI and TCA. Urinary re-excretion rates of the total excreted amounts were 65-70% in TRI, CH and F-TCE groups, about 50% in TCA and 99% in Conj-TCE group. It is possible that all of the substances administered, particularly F-TCE, are metabolized to Conj-TCE in the urinary bladder.     

Metabolism of mephentermine in male guinea pigs and male mice

1. Urinary metabolites of mephentermine (MP), after i.p. administration of MP to male Hartley guinea pigs and mice, were identified by g.l.c.-electron impact (El) mass spectrometry. Excretion of urinary radioactivity, and metabolites of ³H-MP, after i.p. administration, were determined by preparative t.l.c.-liquid scintillation counting.

2. About 27% of the radioactivity administered was excreted in the 24?h urine of guinea pigs, and 36% dose was excreted in 5 days. In mice, about 47% of the radioactivity was excreted in the 24?h urine, and 52% in 5 days.

3. Excretion rates of metabolites detected in the 24?h urine of guinea pigs were phentermine (Ph, 7.8%), a conjugate of N-hydroxyphentermine (N-hydroxy-Ph, 3.6%), p-hydroxyphentermine (p-hydroxy-Ph, 1.0%) and its conjugate (2.9%), and other metabolites (conjugates of MP and Ph, N-hydroxymephentermine (N-hydroxy-MP) and its conjugate, p-hydroxymephentermine (p-hydroxy-MP) and its conjugate, and N-hydroxy-Ph; <1.0%). The rates of excretion for mice were Ph (11.7%), conjugates of p-hydroxy-MP (3.1%), Ph (2.7%) and p-hydroxy-Ph (1.6%), and N-hydroxy-Ph (1.2%) and other metabolites (conjugates of MP and N-hydroxy-Ph, N-hydroxy-MP and its conjugate, p-hydroxy-Ph, and p-hydroxy-MP; <1.0%).

4. These results indicate that MP administered to mice is metabolized mainly to Ph and p-hydroxy-MP by N-demethylation and p-hydroxylation of the parent compound, and in guinea pigs the primary metabolic reaction of MP is N-demethylation producing Ph. This, together with previous findings in rats, shows that there are marked metabolic differences between guinea pigs, mice and rats.     

Absorption, distribution, metabolism and excretion of 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxyphenyl)- 1,4-dihydropyridine (PP-1466) in rats

In this experiment, the absorption, excretion, distribution and metabolism of 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxyphenyl)-1, 4-dihydropyridine (PP-1466) were investigated following oral or intravenous administration, single dose or repeated dose administration using male SLC-Wistar rats and the results of this investigation were summarized as follows: After oral administration of 14C-PP-1466 to rats, the blood level reached the maximum at 1 h and decreased with the biological half-life of about 5 h. The unchanged drug concentration in plasma was 30% of total concentration in plasma and disappeared at 6 h. The high radioactivities in the liver, kidney, fat, lung and adrenal gland were observed after oral and intravenous administration. After oral and intravenous administrations, the excretion in feces and urine during 48 h was 63.0 and 32.4, 58.6 and 41.6%, respectively. Biliary excretion amounted to 57.6 and 46.2% during 48 h, respectively. Six metabolites were found in the urine of rats. Three of them were identified as 2,6-dimethyl-3-carbomethoxy-4-(2-difluoromethoxyphenyl)-5-carboxylic acid pyridine, 2-methyl-3-carbomethoxy-4-(2-difluoromethoxyphenyl)-5-carboxylic acid-6-hydroxymethyl pyridine and its lactonizing analogue. These three metabolites covered 54% of total urinary metabolites. After oral repeated administration for three weeks, the excretion ratio of radioactivity in urine and feces was constant during the administration and no accumulation was observed in rat tissues.     

Comparison of urine analysis and dried blood spot analysis for the detection of ephedrine and methylephedrine in doping control

When the misuse of stimulants is determined in doping control tests conducted during the in‐competition period, athletes are asked to account for the violation of the rules. This study was designed to evaluate whether the urinary threshold values (10 µg/mL) for ephedrine and methylephedrine set by the World Anti‐Doping Agency (WADA) can be exceeded after the oral administration of each substance (25 mg). In addition, the study describes the validity of a liquid chromatography‐tandem mass spectrometric method using dried blood spot testing to detect ephedrine and methylephedrine by comparing it to a quantitative laboratory urine assay. After administration of ephedrine, the urinary concentration of ephedrine did not exceed the threshold at 4–10 h in two subjects, whereas the threshold was exceeded in both the subjects at 12 h after administration. For methylephedrine, the urinary concentrations of all the subjects failed to reach the threshold for up to 10 h after administration. The concentrations reached the threshold at 12–24 h after administration in some volunteers. In contrast, the blood concentrations of ephedrine and methylephedrine reached their maximum levels at 2–8 h after administration. The blood concentrations showed a low inter‐individual variability, and the results suggested that the urinary excretion of ephedrine and methylephedrine can be strongly affected by urine pH and/or urine volume. These facts suggest that urinary concentrations cannot reflect the psychoactive level of ephedrines in circulation. Thus, dried blood analysis might be suitable for the adequate detection of stimulants during in‐competition testing. Copyright © 2015 John Wiley & Sons, Ltd.     

Interaction of bemetizide and indomethacin in the kidney

The effect of a single oral dose of 25 mg bemetizide on renal function without and with concomitant administration of the prostaglandin synthesis inhibitor indomethacin was investigated in ten healthy volunteers during sustained water diuresis. Bemetizide induced a significant increase in urinary sodium and chloride excretion from 196 +/- 30 and 163 +/- 28 mumol/min to 690 +/- 54 and 537 +/- 51 mumol/min (P less than 0.01). This effect occurred in the absence of changes in glomerular filtration rate, urinary excretion of phosphate or the delivery of chloride beyond the proximal nephron to the distal tubules (distal delivery) [(CH2O + CCl)/GFR . 100], but was associated with a significant decrease in distal fractional chloride absorption (DFACl) [CH2O/(CH2O + CCl)] from 0.84 +/- 0.02 to 0.63 +/- 0.02 (P less than 0.01). Bemetizide also increased urinary excretion of prostaglandin (PG) E2. Concomitant indomethacin administration significantly suppressed urinary excretion of PGE2 and markedly decreased urinary excretion of sodium and chloride during control and following bemetizide administration. Indomethacin had no effect on glomerular filtration rate, urinary excretion of phosphate, distal delivery or the urinary excretion of bemetizide but significantly increased DFACl both during control and after bemetizide administration. Our results show that bemetizide as a thiazide-diuretic acts in the diluting segments of the nephron. Indomethacin administration induces retention of sodium and chloride and blunts the renal effects of bemetizide via increased absorption in the diluting segments. The interaction of both drugs most likely represents a pharmacodynamic interaction.     

Pharmacokinetics after discontinuous intravenous administration of azlocillin

In severe, sometimes life-threatening infections azlocillin (Securopen) is administered in single doses up to 10 g in order to increase therapeutic efficacy. Therefore the serum concentrations and urinary excretion of azlocillin were investigated in 2 healthy volunteers and in 11 patients after intravenous injection (5 min) of 2 g followed by intravenous infusion of 2 g/h over 4 h. The serum concentrations increased during infusion in patients up to a median concentration of 317 mg/l. The median serum concentrations decreased down to 94 mg/l at 2 h, 43 mg/l at 4 h and 11 mg/l at 6 h after the end of infusion. 24-h urinary excretion in patients was 54.3%. Serum half-life from the last five serum concentrations (6-10 hours after start of administration) calculated amounts to a median half life of 100 min (range 60-180 min). The study showed, that using this dose and kind of administration high serum concentrations can be maintained over many hours, sufficiently high also for life threatening and difficult-to-treat infections, if administered at intervals of 12 hours.     

Absorption and excretion of 3H-raubasine in human subjects and dogs

The pharmacokinetic behavior of (3,5,6-3H)-raubasine (RAU) was investigated in human subjects after oral administration and in dogs after both intravenous and oral administration. By the oral route RAU peak plasma levels appeared in human subjects after 1 h and in dogs after 2 h. Three-day cumulative urinary excretion was 22% by i.v. route and 13% by oral route in dogs, being 29% in human subjects after oral administration. Three-day cumulative faecal excretion in dogs was 51% by i.v. route and 57% by oral route whilst it was 24% in humans. From a comparison between the urinary excretion values observed after i.v. and oral administration, a RAU intestinal absorption of 59% may be obtained.     

Plasma and urine pharmacokinetics of free and of short-chain carnitine after administration of carnitine in man

To 6 healthy volunteers 30 mg/kg of L-carnitine (1,3-hydroxy-4-N-trimethylamino-butyrate) were injected intravenously and plasma levels (mumol/l) of free and short-chain carnitine were determined at different times between 0.033 and 24 h. The urinary excretion of L-carnitine and short-chain carnitine in 24 h was also measured. After a period of wash-out the subjects received 100 mg/kg of L-carnitine orally and plasma levels were determined between 0.5 and 24 h. The urinary excretion of L-carnitine was measured for a period of 18.5-33 h after treatment. 3 of the volunteers also received 30 mg/kg of L-carnitine orally. Carnitine plasma levels were determined at different times between 0.5 and 18 h, while the urinary excretion of L-carnitine was measured for 48 h following the treatment. The results could indicate the presence of saturation phenomena in the absorption process for the oral doses used; specific research is required to ascertain this phenomena. The transfer of carnitine from central to extravascular volume is relatively rapid, as is its urinary excretion. The short half-life of carnitine and acetyl-carnitine can suggest the use of new forms of administration (slow-release).     

Study of the effects of cicletanine on the renin-angiotensin-aldosterone system

The effect of a single dose of 50 mg of cicletanine on plasma renin activity, plasma potassium and aldosterone, blood pressure, urinary volume and sodium and potassium excretion was compared to the effect of the same dose given for 9 days in eight normal volunteers in metabolic balance on 120-140 mEq of sodium and 50-70 mEq potassium. Following 4 days of this standardized diet, the normal volunteers received their first dose of cicletanine after an overnight fast and blood was collected at 30 min, 2, 4 and 6 h for plasma renin activity and aldosterone. Urine excreted following a modest water load was also collected and analysed over a 6-h period. Following the single dose there was an increase in PRA at 1 and 2 h, while there was no such increase with chronic administration. Plasma aldosterone, however, showed no difference between acute and chronic administration of cicletanine treatment. Also plasma uric acid levels increased with acute but not chronic cicletanine. There were no differences in heart rate and blood pressure responses, nor in urine volume, urinary sodium or potassium excretion, or plasma potassium between the different treatments. This study strongly suggests that the antihypertensive effect of cicletanine is not the result of an increased diuresis, as in this case enhanced urinary electrolyte excretion and increased plasma renin activity and aldosterone would be mandatory following chronic administration. Recent evidence suggests that the dissociation between plasma renin activity and aldosterone is the consequence of an effect of cicletanine on intracellular calcium mobilization. This mode of action would explain both the antihypertensive as well as the aldosterone secretion reducing effect of cicletanine.     

Serum and urine kinetics of rosaprostol in volunteers

The kinetics of rosaprostol (9-hydroxy-19,20-bis-norprostanoic acid, Rosal) and of its metabolite (3-(2-n-hexyl-5-hydroxy-cyclopentyl)propionic acid) has been determined in plasma and in urine of 10 healthy volunteers after oral administration of 500 mg of rosaprostol. The peak of rosaprostol (of 524 ng/ml) appears at 4 h, whereas that of the metabolite (of 503 ng/ml) appears earlier (2 h); therefore the relationship between the two substances does not follow the precursor-successor relationship in plasma and a compartmental model has been used to fit the data. In this model the biotransformation process occurs before entering the central compartment (first-pass effect). The mean half-life of rosaprostol is equal to about 5 h and that of the metabolite is equal to 3 h. All of rosaprostol is biotransformed and only the metabolite is partially eliminated by the urine. The urinary excretion of the metabolite represents only a small fraction of the administered dose. The urinary clearance of the metabolite is equal to 5.3 l/h. The volume of distribution of both substances is equal to 21.2 l.     

Human urinary excretion profile after smoking and oral administration of [14C]delta 1-tetrahydrocannabinol

The urinary excretion profiles of delta 1-tetrahydrocannabinol (delta 1-THC) metabolites have been evaluated in two chronic and two naive marijuana users after smoking and oral administration of [14C]delta 1-THC. Urine was collected for five days after each administration route and analyzed for total delta 1-THC metabolites by radioactivity determination, for delta 1-THC-7-oic acid by high-performance liquid chromatography, and for cross-reacting cannabinoids by the EMIT d.a.u. cannabinoid assay. The average urinary excretion half-life of 14C-labeled delta 1-THC metabolites was calculated to be 18.2 +/- 4.9 h (+/- SD). The excretion profiles of delta 1-THC-7-oic acid and EMIT readings were similar to the excretion profile of 14C-labeled metabolites in the naive users. However, in the chronic users the excretion profiles of delta 1-THC-7-oic acid and EMIT readings did not resemble the radioactive excretion due to the heavy influence from previous Cannabis use. Between 8-14% of the radioactive dose was recovered in the urine in both user groups after oral administration. Lower urinary recovery was obtained both in the chronic and naive users after smoking--5 and 2%, respectively.