Pharmacokinetics, urinary excretion and in vitro metabolism of propiverine hydrochloride (P-4) were studied in rat, dog and monkey.
The binding of P-4 and its active metabolites to serum protein of human and other animal species has been determined by equilibrium dialysis.
1. The bioavailability of P-4 in rats was apparently lower (about 2 %) than that in dogs (about 49%).
2. Based on the results of in vitro biotransformation studies of P-4, the rate of P-4 metabolism in the liver was faster than in any other tissues. The rate of P-4 metabolism changed in the following order dog = monkey < < rat.
3. The main metabolic pathways of P-4 was determined to be as follows : after absorption, P-4 underwent a rapid N-oxidation of the piperidine ring, followed by the depropoxylation of the side chain. The hydroxylation occurred at the ω-1 site of propoxyl side chain, followed by the intramolecular ester exchange, depiperidine ester, to the lactone form.
4. The binding of P-4 to serum proteins varied from 89% to 91%. The extent of binding of the active metabolites, P-4(N→O) and DPr-P-4(N→O) varied from 63% to 83%, from 26 % to 34%, respectively. There were no species related differences in protein binding.
5. In human, the major binding fractions of P-4 were HSA and α₁-AGP. The binding parameters of P-4 to HSA and α₁-AGP were following : binding percent and association constant (K) were 79-83%, 0.5 × 10⁶ (M^-1) for HSA, 96-98%, 4.6 × 10⁶ (M^-1) for α₁-AGP, respectively.

View full abstract

Metabolism of sparfloxacin (5-amino-1-cyclopropy1-7-(cis-3, 5-dimethyl-1-piperazinyl)-6, 8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid), a new synthetic antibacterial agent, was investigated in rats, dogs, monkeys and man after oral administration. Metabolites were isolated and their structure was determined by mass spectrometry and ¹H-nuclear magnetic resonance spectrometry. The results were as follows :
1. The glucuronide conjugate of sparfloxacin(M-1) was found together with the unchanged drug in urine of rats, dogs, monkeys and man, showing no species differences in the metabolism of sparfloxacin. Other metabolites were not detected in the urine of all species.
2. The unchanged sparfloxacin and M-1 were also observed in the plasma and bile of rats and man, while in feces, only the unchanged drug was found.
3. The isolated M-1 in pH 7.4 buffer was slowly hydrolyzed to sparfloxacin at 37°C with a half-life of 82h, indicating that M-1 is a very stable glucuronide among any other conjugates previously reported.

View full abstract

Pharmacokinetics of sparfloxacin (5-amino-l-cyclopropyl-7-(cis-3, 5-dimethyl-1-piperazinyl)-6, 8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, SPFX), a new synthetic antibacterial agent, was investigated in rats, dogs and monkeys after oral and intravenous administration of 5 mg/kg. The results were as follows :
1. SPFX was well absorbed (60-90% of the dose) from the gastrointestinal tract in all species examined. After oral dosing at a dose of 5mg/kg, plasma levels of SPFX in rats, dogs and monkeys reached a peak of 0.67, 1.32 and 0.45μg/ml, respectively, and decreased with apparent elimination half-lives of 3. 5, 8. 2 and 5. 6h, respectively.
2. There were no sex-related differences in the pharmacokinetics of SPFX in rats.
3. The pharmacokinetics of SPFX in rats was not affected with its 7-day consecutive administration.
4. The plasma concentration-time profile in rats with D-galactosamine-induced hepatic disorder was in good agreement with that in normal rats.
5. In dogs, SPFX was well distributed in many tissues at concentrations exceeding the plasma levels, but was poorly distributed in the central nervous system.
6. The glucuronic acid conjugate of SPFX was found together with the unchanged drug in the urine of all species. No metabolites were detected in rat feces.
7. Urinary and fecal excretion in rats after oral dosing accounted for 15.8 % and 81.9% of the dose, respectively. A total amount excreted in the urine was 14.3% of the dose in dogs and 17.3% in monkeys.

View full abstract

Pharmacokinetics of sparfloxacin (5-amino-1-cyclopropyl-7-(cis-3, 5-dimethyl1-piperazinyl) 6, 8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid), a new synthetic antibacterial agent, was evaluated in the healthy male volunteers. The subjects were given a single oral dose (100, 200 and 400mg, each of 6 subjects) and a repeated oral dose (200mg×2/day for 7 days and 300mg × 1/day for 7 days, each of 6 subjects). The results were as follows :
1. Mean plasma levels of sparfloxacin reached maximum concentrations at 4h after single dosing of 100, 200 and 400mg and were dose-related with corresponding values of 0.34, 0.58 and 1.18μg/ml, respectively, followed by a slow decrease with apparent half-lives of 15.8 ?? 16.9h. Plasma levels of sparfloxacin glucuronide accounted for about 30-40% of the unchanged drug.
2. Urinary excretion of the unchanged drug and its glucuronide during 72 h after single dosing accounted for 12 ?? 13% and 28 ?? 31% of the dose, respectively. In feces, 51% of the dose was excreted as unchanged drug, and no metabolites were detected after dosing of 200mg.
3. There were no significant changes in the plasma concentration-time profile and the fraction of urinary excretion between single and multiple doses, indicating that the pharmacokinetics of sparfloxacin in man was not affected by its multiple administration.
4. Plasma levels and urinary excretion were not significantly altered after dosing with or without food.
5. An average of 38% of the unchanged drug was bound to plasma protein.

View full abstract

The intestinal absorption characteristics of sparfloxacin (5-amino-1-cyclopropyl-7-(cis-3, 5-dimethyl-1-piperazinyl)-6, 8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, SPFX), a new quinnlone antibacterial agent, was investigated in rats using the in situ ligated loop method and the everted jejunum uptake method in vitro. SPFX was well absorbed from the duodenum, jejunum, ileum and colon, but not from the stomach. The 15-min absorption of SPFX from the jejunum loop was found to be saturable : about 50% of the dose being absorbed at doses of 0.1-lumol/loop and about 15% at 10-30umol/loop. Di-, tripeptides and cyclacillin significantly inhibited the absorption of SPFX by about 40 %, but amino acids did not affect the SPFX absorption. The in vitro uptake of SPFX into the rat everted jejunum was reduced by lowering incubation temperature and by the addition of thiol reagents, di-, tripeptides and aminop-lactam antibiotics. Glycylglycine competitively inhibited the uptake of SPF X. These results suggest that SPFX can be transported by a common dipeptide carrier-mediated system present in the intestinal mucosa. About 40% of SPFX is considered to be absorbed by this system, resulting in good absorption of SPFX from the intestinal tract after oral administration.

View full abstract

The renal excretion mechanism of sparfloxacin (5-amino-1-cyclopropyl-7-(cis-3, 5-dimethyl-1-piperazinyl)-6, 8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid) was studied in rats by using the stop -flow method and the renal clearance method. The results were as follows :
1. Sparfloxacin was scarecely secreted from the proximal tubules of the nephrons, but it was reabsorbed at the distal tubules.
2. Fifty-five percent of sparfloxacin present in the plasma were filtered from the glomerulus of the nephrons, and a half of that present in the filtrate was reabsorbed at the distal tubules and a residual half was excreted in urine.
3. The renal handling of sparfloxacin differs from those of other quinolones that show tubular secretion, resulting in the prolonged plasma elimination half-life of sparfloxacin.

View full abstract

The effect of sparfloxacin on the theophylline pharmacokinetics was investigated in rats.
1. The plasma levels and pharmacokinetic parameters of theophylline after a single oral dose (15mg/kg) in rats treated orally with sparfloxacin (100 mg/kg, 3 times) were not significant different from those in control rats, not treated with sparfloxacin.
2. After multiple oral administration of theophylline (15mg/kg, twice/day) for 3 days, the maximum plasma concentration of theophylline was 20.2μg/ml in the sparfloxacin-treated rats (100mg/kg, 3 times/day for 3 days) and 21.0μg/ml in the control rats, and there was no effect of the sparfloxacin treatment.
3. In the 24-hr urinary excretion of theophylline after a single oral dose (15mg/kg), there was no significant difference between the sparfloxacin-treated (100mg/kg, 3 times) and control rats. Moreover, the sparfloxacin treatment also did not affect the amount of the theophylline metabolites excreted in urine.
4. In conclusion, sparfloxacin shows no significant effect on the pharmacokinetics of theophylline in rats.

View full abstract

Pharmacokinetic studies on time -course of blood levels, tissue distribution and excretion of CPT-11, a new antitumor agent, were performed in male rats after a single intravenous administration of ¹⁴C-labeled CPT-11 at a dose of 4 mg/kg, 10.62mg/kg and 20mg/kg.
1. The blood level of radioactivity at 5min after administration of the dose of 4mg/kg, 10.62mg/kg and 20mg/kg corresponded to 2.21μg/ml, 4.82μg/ml and 11.70μg/ml, respectively. The blood concentrations after these doses decreased multi-exponential ly in similar manner with the half-lives of 0.6-0.8 hr, 2hr and 16hr, respectively. The area under the concentration-time curve increased nonlinearly as the dose increased.
2. The radioactivity was well distributed in all the tissues, especially in the kidney, adrenal, thyroid, pancreas and lung. The concentrations in these tissues were 13 to 25 times higher than that in the plasma. The radioactivity in most tissues, except skin, disappeared in a similar manner as that in the plasma.
3. Within 72hr after the administration, the radioactivity was excreted into the urine and feces at the rate of 22. 2 and 76. 4% after the dose of 4mg/kg, 22.6 and 77.1% after administration of 10.62mg/kg, and 27.2 and 67.0% following administration of 20mg/kg, respectively.
4. The pharmacokinetic profile of CPT-11 was also estimated by the whole body autoradiography.

View full abstract

Pharmacokinetic studies on metabolites pattern and their concentrations in the serum and tissues were performed in male rats after a single intravenous administration of ¹⁴C-CPT-11 at a dose of 10.62mg/kg using the HPLC method.
1. The unchanged drug, CPT-11, was detected as the main compound in the serum and tissues, and accounted for almost all the concentration of total radioactivity at early time after dose.
2. The concentrations of active metabolite, SN-38, in the serum and tissues were very low, but disappeared relatively more slowly than CPT-11. 3. The ratios of SN-38 AUC/CPT-11 AUC were 0.079 in the serum, 0.018 in the liver and intestinal tissue, and 0.004 in kidney, respectively. The relatively high concentration of SN-38 in the serum and liver must be ascribed to high esterase activity in these tissues, and that in the intestinal tissues could be ascribed not only to the esterase activity, but also to the biliary excretion of SN-38 and SN-38-glucuronide into intestine.

View full abstract

Pharmacokinetic studies on time-course in the blood, tissue distribution, excretion and metabolism of CPT-11, a new anti-cancer agent, were performed in rats following a single intravenous administration of ¹⁴C-CPT-11 (PP) at a dose of 10mg/kg.
1. Piperidinopiperidine, UM-1, was detected in the urine as the main metabolite originating from the side-chain part of CPT-11.
2. The urinary and fecal excretions of radioactivity within 72hr after dosing were 22.6 and 77.1% after administration of ¹⁴C-CPT-11 and 41.2 and 54.5% following administration of ¹⁴C-CPT-11(PP), respectively. The metabolites from the side chain part were assumed to be excreted mainly into the urine.
3. The plasma and tissue concentrations of radioactivity after dosing of ¹⁴C-CPT-11 (PP) disappeared more slowly than that after administration of ¹⁴C-CPT-11. The metabolites from the side-chain part were assumed to have higher affinity to plasma and tissues, however the specific accumulation of the metabolites derived from the side-chain part were not detected in any tissues.

View full abstract