The pharmacokinetics of neostigmine and 3-hydroxyphenyltrimethyl- ammonium in the rat: dose-dependent effects after portal vein administration.

1 The elimination kinetics of [(14)C]-neostigmine iodide and [(14)C]-3-hydroxyphenyltrimethyl-ammonium iodide (3-OH PTMA) have been studied in the rat.2 The presence of a renal secretory pathway for neostigmine and 3-OH PTMA has been confirmed.3 For neostigmine and 3-OH PTMA, at a given dose level, the fraction of the dose eliminated unchanged was reduced and the metabolite fraction was increased after portal vein administration when compared to jugular vein administration. This indicates that both compounds are subject to extensive metabolism during the first passage through the liver.4 Neostigmine was eliminated by dose-independent kinetics after jugular vein administration but dose-dependent after portal vein administration. In the latter case the fraction eliminated as neostigmine increased with increasing dose. This increase was not accompanied by any change in the fraction of the metabolites eliminated.5 After portal vein administration of 3-OH PTMA, the fraction of the dose eliminated as 3-OH PTMA also increased with increasing dose. This change was accompanied by a decrease in the fraction of the metabolites eliminated which were excreted at a constant rate.

Distribution kinetics and intestinal absorption of practolol in the rat.

1. After intravenous injection of practolol the blood concentration-time curve is fitted by a bi-exponential function. A two compartment open system model is therefore a minimal requirement in order to describe adequately the distribution of the drug in the body.2. The parameters of the two compartment model for practolol were determined. The mean values for the ;fast disposition' half life and the ;slow disposition' half life were 0.5 min and 13.3 min, respectively.3. The rate constants of distribution and elimination were similar in different animals. The volume of the central compartment was related to the weight of the animal.4. The absorption of practolol from an intestinal site was measured by its appearance in the blood. The rate constant for this process was estimated to be 0.03 min(-1).

Determination of the renal clearance of inulin in rats: lowered values at low urine flow rates.

The renal clearance of inulin (ClIN) was measured in anaesthetized male rats using a continuous intravenous infusion method.ClIN was independent of urine flow rate provided this was greater than 0.03 ml/minute.At flow rates lower than this, CIIN was reduced and appeared to correlate with the rate of flow.In experiments where a constant kidney function is required. e.g., pharmacokinetic studies, it is advisable to maintain urine, flow rates in the rat above 0.03 ml/minute.

The pharmacokinetics of pyridostigmine and 3-hydroxy-N-methylpyridinium in the rat: dose-dependent effects after portal vein administration.

1 The elimination kinectis of [14C]-pyridostigmine iodine and [14-C-methyl]-3-hydroxypyridinium bromide (3-OH NMP) have been studied in the rat. 2 For pyridostigmine, at a given dose level, the fraction of the dose eliminated unchanged was reduced and the metabolite fraction was increased after portal vein administration when compared to jugular vein administration. This indicates that pyridostigmine is subject to metabolism during the first passage through the liver. 3 When doses of pyridostigmine 1.25 mumol/kg and higher were injected via the portal vein, the proportion excreted in urine as unchanged drug remained constant; in contrast, the percentage of the dose eliminated as the metabolite was significantly reduced. This indicates that a dose-dependent process is involved in the urinary excretion of 3-OH NMP. 4 This conclusion was supported by studies involving the portal and systemic venous injection of 3-OH NMP at different dose levels. After 4 h, approximately85% of the lowest dose was eliminated unchanged in ug this period. The proportion of the dose eliminated in urine was not related to the route of administration. 5 After the injection of pyridostigmine into the jugular vein, the initial rate of drug excretion fell rapidly for approximately 10 min; in contrast, after injection into the portal vein, the rate of excretion of the drug rose to a maximum at 30 minutes. This suggests that the hepatoportal system behaves as a distinct region during the distribution of this drug.

The disposition of the synthetic prostaglandin analogue cloprostenol ('Estrumate') in the rat and marmoset.

1. Following subcutaneous administration of the synthetic prostaglandin analogue [14C]cloprostenol to the rat (200 micrograms/kg), the dose was quantitatively recovered from the excreta: 52% of the dose was present in the urine and 43% in faeces. After intravaginal administration (200 micrograms/kg) 42% of the dose was recovered from the excreta, equally divided between urine and faeces, and 40% (range 25--66%) of the dose was recovered from the site of application. The radiolabelled compounds present in faeces were eliminated initially via the bile. 2. The max. observed plasma concn. of total 14C in the rat was 84 ng equiv./ml at 30 min after subcutaneous administration of cloprostenol (200 micrograms/kg). A component which co-chromatographed with cloprostenol on t.l.c. was rapidly cleared from plasma with a half-life of 54 min. After intravaginal administration of cloprostenol (200 micrograms/kg), low and persistent plasma concn. of 14C were detected. 3. The metabolic fate of cloprostenol in the rat and marmoset has been studied with radiolabelled and non-labelled drug mixed such that fragments detected by mass spectrometry exhibited characteristic 12C:14C isotope clusters. Metabolites derived from cloprostenol contained these characteristic doublets. 4. In the rat cloprostenol is metabolized by beta-oxidation to tetranor-cloprostenol. Unchanged cloprostenol and a conjugate of tetranor-cloprostenol were minor urinary metabolites. In the rat biotransformation of cloprostenol in the cyclopentane ring occurred; the tetranor acid of 9-keto-cloprostenol was identified in urine. In the marmoset unchanged cloprostenol and dinor-cloprostenol were major urinary components.

The metabolic fate of the synthetic prostaglandin cloprostenol ('Estrumate') in the cow: use of ion cluster techniques to facilitate metabolite identification.

The metabolic fate of the synthetic prostaglandin cloprostenol ('Estrumate') in the cow has been studied. Following intramuscular administration of 0.5 mg and 10 mg of [14C]cloprostenol to cows urinary excretion accounted for 58.2% and 56.3% of the dose respectively. Unchanged cloprostenol and its tetranor acid, probably formed by beta-oxidation, were the major components identified in urine. The tetranor acid was also present as a glucuronide conjugate. This synthetic prostaglandin analogue is apparently a poor substrate for the enzymes 15-hydroxyprostaglandin dehydrogenase and 13,14-reductase, which are responsible for the rapid metabolic deactivation of endogenous prostaglandins, as no components identified in urine were found to have undergone metabolic attack at the C-15 atom in the cloprostenol molecule.

The metabolism of ICI 118,587, a partial agonist of beta 1-adrenoceptors, in mice, rats, rabbits, dogs, and humans.

The absorption, metabolism, and excretion of 14C-labeled xamoterol (ICI 118,587) has been examined in mice, rats, rabbits, dogs, and humans. There was incomplete absorption by all species after oral administration, ranging from 9% by humans to 36% by dogs. Most of the absorbed radioactivity was eliminated within 24 hr of administration and the renal route predominated. Conjugates of the parent compound were the only observed metabolites in urine, the phenolic glucuronide being the principal animal metabolite and the phenol sulfate being the only human metabolite. There were marked interspecies variations in metabolite patterns and dogs were the only animal species in which the sulfate metabolite was detected. Comparison of the urinary metabolite patterns also showed higher output of the conjugates after oral administration than after intravenous administration, indicating that first pass metabolism was taking place. Little significant change in absorption or metabolism was seen over a range of oral doses; in rats, some saturation of the glucuronide-conjugating mechanism was observed but the sulfate-conjugating mechanism showed little, if any, diminished capacity at high dose levels in dogs. The use of fast atom bombardment mass spectroscopy for the determination of the molecular weight of conjugates is described.

Ion cluster techniques in drug metabolism: an example of the use of mixtures of the [12C]:[14C] isotopic forms of the synthetic prostaglandin cloprostenol ('Estrumate') to facilitate metabolite identification.

The synthetic prostaglandin analogue cloprostenol has been prepared radiolabelled with 14C. The isotopic abundance of 14C at position C-15 was greater than 90% of the theoretical maximum. We have utilizted the high abundance of the 14C isotope for metabolism studies by preparing mixtures of [12C]:[14C]cloprostenol such that fragments detected by mass spectrometry contained characteristic isotope clusters analogous to those often obtained using stable isotopes.