This study was undertaken to determine plasma levels, metabolism, urinary excretion of propentofylline after intravenous (i. v.) and oral (p. o.) administration of 3 mg/kg to rabbits.
Following i. v. administration the plasma level of the unchanged propentofylline declined rapidly in a biphasic manner with the half-lives of α- and β-phases of 4.6 and 21.4 min, respectively. The major plasma components were acid (carboxyl) metabolites A80 2751 and A80 2831 and a hydroxyl metabolite A72 0287. Only small amounts of hydroxyl metabolites A79 2442 and A79 2438 were detected. In the plasma, after p. o. administration the parent compound was not found and only the above 2 acid metabolites were present at high concentrations. The ratio of p. o. to i. v. AUCs combined for the 2 acid metabolites was approximately 0.9, suggesting that propentofylline was well absorbed from the gastrointestinal tract.
A80 2751, A80 2831, and A79 2438, mainly the former 2 acid metabolites, accounted for nearly 100 % of the total urinary excretion following i. v. and p. o. administration; the excretion of the parent compound to the urine was minimal. No conjugates were present in the urine. The urinary recovery within 48 hr was about 23 and 26 % of the given dose after i. v. and p. o. administration, respectively.

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The metabolites, metabolizing organs of oxybutynin and its effect on the induction of drug metabolizing enzymes were investigated in rat, dog and human after oral administrations of oxybutynin and following the results were obtained.
1. Eight metabolites of oxybutynin and their glucuronide were identified in the dog and human urine after oral administration.
2. About 18 %, and 8.7 to 27.5 % of the administrated dose were excreted as a metabolites to urine in dogs and humans, respectively.
3. It was presumed that oxybutynin was metabolized by the following four pathways; a) de-ethylation b) hydrolysis of ester c) hydroxylation at 3' and 4' positions on cyclohexyl ring and d) conjugation of each metabolites.
4. The highest metabolic activity for oxybutynin was shown in the rat liver.
5. The induction of drug metabolizing enzymes by oxybutynin, administered orally every day for 8 days, was not found.

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Foeto-placental transfer and excretion with milk of ¹⁴C-timiperone was studied in the pregnant and lactating rats after a single oral administration of ¹⁴C-timiperone at a dose of 0.5 mg/kg. ³H-Haloperidol was also used as a reference compound.
1. On day 18 th of gestation, the concentration of radioactivity in the fetus 4 hr after administration of ¹⁴C-timiperone, was 1.7-1.8 times higher than that in the maternal blood, indicating that timiperone and its metabolites were easily transferred across the placenta to the fetus due to their lipophilicity.
In case of the feoto-placental transfer of ³H-haloperidol, much higher concentration of radioactivity in the fetus was observed, as compared with that of ¹⁴C-timiperone.
2. Following oral administration of ¹⁴C-timiperone to the lactating rats on day 10 th post partum, the milk levels of radioactivity increased gradually, and were 6.6-11.5 times higher than those in the maternal blood, indicating that timiperone and its metabolites were easily transferred to the milk from the blood.
On the contrary, in the ³H-haloperidol-treated lactating rats, the milk levels of radioactivity were almost the same as those in the maternal blood, showing low transfer of ³H-haloperidol and its metabolites to the milk.

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The in vivo and in vitro metabolism of argipidine, the potential anti-thrombin agent, was studied in rats. Four metabolites were isolated from the bile of rats after intravenous administration of ¹⁴C-argipidine and from the incubation medium of argipidine supplemented with rat liver 9000 × g supernatant or rat hepatic microsomes, and were identified or presumed to be as follows; aromatized derivative of 3-methyltetrahydroquinoline (3 MTHQ) ring of argipidine (M-1), cis and trans forms of 4-hydroxy derivatives of 3 MTHQ ring (M-2 and M-3, respectively) and N-hydroxy derivative of 3 MTHQ ring (M-4). When added to rat hepatic microsomes, M-4 was also metabolized to M-1, and the conversion was NADPH and oxygen dependent. These findings suggested the aromatization of argipidine in the rat hepatic microsomes was stepwise oxidative reaction, with N-hydroxylation of argipidine as the initial step. And also, it was suggested that two independent pathways were present for biotransformation of argipidine in rat hepatic microsomes. Namely, M-2 and M-3 were produced by the catalysis of cytochrome P-450 monoxygenase system, and M-4 was produced by the catalysis of flavin-containing monoxygenase.

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Plasma level profile, distribution, metabolism and excretion of argipidine were investigated in male and female rats after single or consecutive intravenous administration of ¹⁴C-argipidine.
1. Concentrations of total radioactivity and unchanged argipidine in plasma were decreasing rapidly with the helf-lives of about 4 min (T_1/2α) and 80 min (T_1/2β), and about 3 min (T_1/2α) and 20 min (T_1/2β), respectively, after single dosing.
2. The liver, kidney and gastrointestinal tract were the organs containing high radioactivity. After consecutive administration of ¹⁴C-argipidine to male rats for 21 days, no significant accumulation of radioactivity occured in any tissue.
3. Major urinary and fecal metabolite was the aromatized derivative of tetrahydroquinoline ring of argipidine (M-1).
4. Approximately 90 % of the administered radioactivity was recovered from the urine and feces within 24 hr after single and consecutive dosing of ¹⁴C-argipidine. The cumulative biliary excretion of radioactivity was about 90 % within 48 hr.

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Microanalyses of bestatin and p-hydroxybestatin, possible therapeutic drugs for muscular dystrophy, in mouse muscle and serum have been accomplished by high-performance liquid chromatography with fluorescence detection. The drugs are extracted into dilute acetic acid for bestatin and perchloric acid for p-hydroxybestatin. The extracts are converted to fluorescent derivatives by means of the previously reported techniques, and the derivatives are separated on a reversed-phase column (TSK gel ODS-120T) with isocratic elution, respectively. The methods permit the quantification of bestatin and p-hydroxybestatin at concentrations of as low as 900 ng and 130 ng per g in mouse muscle, and 200 ng and 30 ng per ml in mouse serum, respectively. It was found that, in oral administration in the same doses (50 mg/kg each), bestatin is distributed at higher concentrations to the muscle than p-hydroxybestatin, though the concentrations of the drugs are almost equal in the serum.

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The Bayesian forecasting techniqe has recently been introduced as a new area of clinical pharmacokinetics, and is now becoming more powerful and useful tool to assist dosage adjustment for individual patients in therapeutic drug monitoring practice (TDM). This newer, and a sophisticated method is based on the principles of Bayes' theory and Maximum Likelihood Estimation, and utilizes prior information on the distribution of population pharmacokinetic parameters, means and variances, as well as drug serum concentrations. With the aid of a small computers, Bayesian weighted least square fitting method can work with at least one observation, whereas standard weighted least square fitting methods need more than four or five observations for accuracy and precision. The Bayesian approach in clinical pharmacokinetics involves the prediction of pharmacokinetic parameters, dosage regimens, and serum drug concentrations. The application of Bayesian procedure has been studied for several drugs such as digoxin, theophylline, aminoglycosides, phenytoin, and lidocaine. In this paper, I present a review of the theoretical background of Bayesian procedure, the applications in therapeutic drug monitoring practice, and the remaining problems to improve the predictive performance.

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Organophosphorus insecticides are one of the biggest groups of pesticides and most of them have sulfur directly connected with phosphorus atom. Thionophosphorus compounds exert their insecticidal activity by inhibiting acetylcholinesterase (AChE) after conversion to their oxon forms. This conversion is mediated in vitro by the mixed function oxidase system (mfo), which also gives apparent hydrolysis products of thiono compounds. Studies on the origin of oxygens incorporated into the products as a result of mfo and peracid oxidation gave the evidence for phosphorus oxythionate intermediate as the initial oxidation product of thiono compounds. The involvement of unstable phosphorus oxythionate in biological and abiotic reactions can be indicated by the presence of its conversion product, phosphinyl disulfide.
Thiono compounds often isomerize to thiolo compounds not only under abiotic conditions such as heat and light, but also in the presence of mfo. Certain thiolophosphorus compounds inhibit AChE in vivo, but not in vitro, indicating that an activation mechanism is involved, which is found to be the oxidation on thiolo sulfur. Activated form is unstable and is suspected to be the S-oxide.
Transformation of thiophosphorus compounds is understandable in terms of the involvement of such unstable and reactive intermediates, and such information will be useful in the designing of a new phosphorus insecticide.

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