Metabolic disposition of a new cephalosporin, DQ-2556, was studied during and after consecutive intravenous doses of ¹⁴C-labelled DQ-2556 once a day for 21 days.
1. The mean blood concentrations at 2h after each dose showed a steady-state plateau with a large standard deviation. However, those at 24h after each dose increased with time until the 18th dose reaching the plateau. After the last dose blood concentration initially declined smoothly, but later, at low concentration, it lasted longer than that observed in single dose study.
2. Tissue concentrations were nearly proportional to the blood concentration except in the spleen. The concentration in the spleen steadily increased during multiple dosing and reached to the same level as that of the kidney. Then, it sustained longer than that of blood.
3. After each dosing, more than 95 % of the dosed radioactivity was recovered in urine and the other part in feces during next 24h. Approximately 80% of the radioactivity excreted into urine was composed of DQ-2556.
4. These findings revealed that the metabolic disposition of DQ-2556 in multiple dosing could be characterized as repetition of that of single dosing except that a little amount of the drug and/or metabolites were excreted slowly.

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¹⁴C-Labelled or non-labelled zolpidem hemitartrate, a new hypnotic drug, was given intravenously, intraportally or orally to male rats and its pharmacokinetics was examined. The results are summarized as follows.
1. After intravenous dosing of 3.29 mg/kg of zolpidem hemitartrate, the zolpidem in the plasma disappeared biexponentially with a terminal elimination half-life of 1.11 hours. After oral dosing of 0.66, 3.29 or 16.45mg/kg, zolpidem was absorbed rapidly from the gastrointestinal tract with T_max of 5 minutes. Linear relationships between AUC, C_max and the dose were observed, indicating that the pharmacokinetics of zolpidem after oral dosing is linear.
2. The bioavailabilities of zolpidem after oral and intraportal dosing were 45.8 and 46.2%, respectively, suggesting that the oral absorption of ¹⁴C-zolpidem was almost complete and that about 54% of oral dose might undergo first-pass matabolism in the liver.
3. Thirty minutes after oral dosing of 3.29mg/kg of ¹⁴C-zolpidem hemitartrate, the tissue concentrations of radioactivity in the liver, kidneys, adrenal gland, brown fat, urinary bladder, stomach and small intestine were higher than those in the plasma. 24 hours after dosing, the concentrations of radioactivity in the liver, kidneys, skin and large intestine were 13 ?? 52ng eq/g, but no radioactivity was detected in the other tissues.
4. M-I, a carboxylic acid derivative of zolpidem, was a main metabolite in the plasma, urine, feces and bile of rats. This shows that the main metabolic pathway of zolpidem in rats is methyl oxidation on the phenyl moiety leading to alcohol and carboxylic acid derivatives.
5. 23.7 % of the dosed radioactivity was excreted in the urine and 74.2% in the feces up to 120 hours after oral dosing. Sixty seven % of the dosed radioactivity was excreted in the bile of bile-duct cannulated rats up to 48 hours after oral dosing. Thus, the principal excretion route of radioactivity in rats was the feces via the bile.

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The ¹⁴C-labelled compound of zolpidem hemitartrate, a new hypnotic drug, was given orally in a dose of 3.29mg/kg to male rats once a day for a maximum of 28 days, and its absorption, distribution, metabolism and excretion were examined. The results are summarized as follows.
1. Area under the blood radioactivity-time curves (AUCs) up to 24 hours after the 1st, 7th, 14th, 21st and 28th dosing were 1.74, 1.35, 1.92, 1.73 and 2.14μg eq.hr/ml respectively. Since there was no the difference among AUCs after the 14th, 21st and 28th dosing, the blood radioactivity was considered to have reached a steady state. The increase of AUCs during multiple dosing was of low extent because those after the 14th and 28th dosing were only 1.1 and 1.2 times higher than those after the 1st dosing.
2. Tissue to plasma concentration ratios of radioactivity after the 14th or 21st dosing were almost constant in many tissues including the blood, lung, liver, kidneys and skin whose the concentrations of radioactivity were higher than in the plasma. This showed that the tissue radioactivity was probably reaching a steady state after the 14th or 21st dosing.
3. The disappearance of radioactivity after the 28th dosing was slow er in the kidneys, spleen and skin than that in the plasma. Seventy two hours after the last dosing, however, the concentrations of radioactivity in these tissues were less than 1 % of the 5 min-value, and no radioactivity was detected at 70 days.
4. After the 28th dosing, the zolpidem was not detected in the urine and feces, and M-I accounted for 57.4 and 59.0% of radioactivity excreted in the urine and feces, respectively. Each amount of M-II ?? M-V in the excreta was 1/10 of that of M-I. The metabolism of zolpidem was unaffected by multiple oral dosing (28 times).
5. Urinary and fecal excretion of radioactivity was almost constant during multiple oral dosing.

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¹⁴C-Zolpidem hemitartrate, a new hypnotic drug, was given orally in a dose of 3.29mg/kg to pregnant and lactating rats and its transfer into the fetus and milk was studied. The results are summarized as follows.
1. After oral dosing to a rat on day 18 of gestation, the radioactivity in the fetus was lower than that in the maternal blood. The radioactivity in the fetal tissues declined rapidly, and no radioactivity was detected 48 hours after dosing.
2. The whole body autoradiograms of rats, which were given the ¹⁴C-labelled compound orally on days 13 and 18 of gestation, showed that the radioactivity in the fetus was lower than that in the maternal blood and that the distribution of radioactivity to the fetus was higher in the perinatal period than in the organogenic period.
3. Thirty minutes after oral dosing to lactating rats, the radioactivity in the milk reached a maximum of 267ng eq/ml, and then declined with a half-life of 4.9 hours up to 24 hours. The radioactivity levels in the milk were almost the same or lower than those in the plasma up to 4 hours after dosing, but were 1.1 ?? 1.8 times higher thereafter. The ratio of AUCm to AUCp, which was calculated from the concentrations of radioactivity in milk and plasma respectively, was about 0.65. This suggested that zolpidem and/or its metabolites were less easily transfered into the milk.

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In vitro and in vivo protein binding of zolpidem and its transfer into the blood cells were studied in rats, monkeys and humans. The results are summarized as follows.
1. In a range of 50 to 5000ng/ml, the in vitro percent binding of zolpidem to serum proteins in rats, monkeys and humans was 86.6 ?? 86.9, 92.4 ?? 93.9 and 94.5 ?? 96.0%, respectively.
2. Zolpidem was bound to two classes of sites with different affinities of human serum albumin and α₁-acid glycoprotein(AGP). The association constants (Ka, M^-1) and binding capacities (NP, M) of zolpidem to these proteins were as follows.
albumin : Ka₁=1.8×10⁵, N₁P=2.9×10^-6, Ka₂=4.2×10³, N₂P=2.1×10^-4
α₁-AGP : Ka₁=6.0×10⁵, N₁P=6.3×10^-6, Ka₂=2.0×10⁴, N₂P=2.5×10^-5
3. The percent binding of zolpidem in 40mg/ml human albumin solution was 83.4 ?? 85.5% and was almost constant over a range of 50 ?? 5000ng/ml. Zolpidem also was highly bound to human α₁-AGP(1mg/ml) but the percent binding of the drug decreased from 83.1% at 50ng/ml to 55.5% at 5000ng/ml. On the other hand, the percent binding of zolpidem in 16mg/ml human globulin solution was 19.5 ?? 21.6%, lower than those in human albumin and α₁-AGP solutions. Consequently, albumin and α₁-AGP would be responsible for the binding of zolpidem to human serum proteins.
4. The in vivo percent binding of zolpidem was 83.2 ?? 83.8% in rat plasma and 96.0 ?? 96.3% in human plasma. These bound fractions were almost the same as the in vitro bound fractions measured simultaneously, indicating that the in vivo plasma protein binding of zolpidem in rats and humans would not be affected significantly by its metabolites.
5. The transfer rates of zolpidem into the blood cells were 31.6 ?? 36.1% for rats, 30.8 ?? 36.6% for monkeys and 17.5 ?? 18.5% for humans, and no a significant correlation between the free fractions in the plasma and the transfer rates into the blood cells was observed.

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After the pretreatment with the potassium iodine containing drinking water, so called iodine-block, the absorption, distribuion, and excretion of radioactivity in rats were observed compared with those in the non-treated (control) rats after intravenous injection of ¹²⁵I-NaI. Consequently, the differences are found as follows ;
1) The change of the radioactivity level in plasma of the iodineblock rats was slightly different from that of the control through 8hr after the injection. From 8hr to 24hr, the plasma levels were remarkably different ; rapid decline was observed in the case of iodine-block rats. Since 24hr, a similar half life was found in each condition, though the curve of the iodine-block was about 1/15 of the control.
2) A few % of the total radioactivity in plasma was found in the acid insoluble fraction through an early period after the injection. After that, the ratio in the acid insoluble fraction increased with time elapsed, and its ratio reached about 40% in the case of the iodine-block, and about 70% for the control.
When the plasma samples 5min and 2hr after the injection were subjected to electrophoresis, the radioactive fraction was found to be present in the albumin fraction.
3) The ¹²⁵I-NaI was recovered mainly in urine. The cumulative excretion percent of the dose for 72hr was about 98% for the iodine-block rats, though it was about 74% for the control. The remaining fractions were retained mostly in the body, but a slight fecal excreti on was also observed.
4) Biliary excretion of the radioactivity within 48hr after the injection was 34% and 27% for the iodine-block and the control, respectively.
5) The autoradiographic data 5min after the injection indicated a saturated photo density over the stomach contents, kidney and urinary bladder. And a relatively higher density over the skeletal muscle was observed in the case of the iodine-block rat than the control rat. Fourty eight hours after the injection, saturated density over the thyroid in control rats was present, but the iodine-block rat did not show any density over the whole body section.
The radioactive proteins of the thyroid were separated by the electrophoresis. The results indicated that remarkable radioactivity was associated with a thyroglobulin spot.

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We studied the pharmacokinetics of EPOCH after subcutaneous administration to male rats and dogs. The EPOCH concentrations in samples were measured by RIA.
1. In rats given EPOCH subcutaneously at the doses of 1, 5 and 25μg/kg, the concentrations of EPOCH reached the peak at 8 to 12 hours after dosing and declined monoexponentially with a half-life ranging from 7.52 to 10.89 hours. MRT of EPOCH after sc dosing ranged from 15.82 to 17.71 hours at any dose levels. F value (AUCsc; AUCiv), which ranged from 0.45 to 0.64, tend to increase as dose increase. Cumulative urinary excretions within 48 hours after dosing were 2.7, 1.2 and 0.9% of dose at 1, 5 and 25μg/kg.
2. In male Beagle dogs given EPOCH subcutaneously at the dose of 5μg/kg, pharmacokinetic parameters of EPOCH were obtained as follows ; C_max was 22.37±2.10ng/ml, T_max was 6.50±2.50h, AUC was 544.32±22.25ng·h/ml, MRT was 23.25±1.55h, and T_1/2 was 12.71±0.47h. F value was 0.46. Cumulative amount of EPOCH excreted in urine for 72h was 0.32±0.14% of dose, and renal clearance was 0.39±0.17ml/h/kg.
3. The molecular profile of immunoreactive materials, identified by gel filtration in plasma samples from rats and dogs given EPOCH subcutaneously, showed the single peak corresponding to the standard EPOCH at any sampling times. These results suggested that the immunoreactive material detected by RIA represented the unchanged EPOCH, and that no immunoreactive metabolite might be present in plasma and urine samples of rats given non-labelled EPOCH subcutaneously.

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We studied the absorption, distribution, excretion and metabolism of ¹²⁵I-EPOCH after single subcutaneous administration to rats.
1. The levels of immunoreactive rad ioactivity reached the maximum at 8 to 12 hours after dosing and declined monoexponentially with a half-life ranging from 5.77 to 7.47 hours at the doses of 0.5, 1, 5 and 25μg/kg. The MRT of immunoreactive radioactivity after sc dosing ranged from 13.83 to 17.01 hours at any dose levels. F value (AUCsc/AUCiv), which ranged from 0.31 to 0.48, tend to increase in proportion to the administered dose.
2. Most of tissues showed the highest level of total radioactivity at 10 hour after dosing. The level of radioactivity in tissues were lower, than that of serum, except the thyroid gland whose level was the highest.
They declined parallel with disappearence of the radioactivity in serum. The level of radioactivity in brain was extremely low. The elimination half-life of radioactivity from the injection site was calculated to be 9h and 1.97% of the dose still remained there at 48 hour.
3. Until 96h after sc administration of ¹²⁵I-EPOCH at the dose of 1μg/kg, urinary excretions of total, the TCA-precipitable and the immunoreactive radioactivity were 75.89%, 0.35%, 0.05%, respectively. Fecal excretion of total radioactivity was 2.97%, until 96h after dosing.
4. Gel filtration of the plasma showed that the radioactivity of low molecular weight was iodo ion, and that related to radioactivity of high molecular weight appeared mainly as an unchanged ¹²⁵I-EPOCH.

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We studied the absorption, distribution and excretion of radioactivity after 4 times multiple subcutaneous administrations of ¹²⁵I-EPOCH at an interval of 48 hours.
1. Plasma levels of immunoreactive radioactivity at 10h and 48h following each multiple administration did not change during the experimental period. There were no pronounced differences in pharmacokinetics between first and fourth administration.
2. The levels of radioactivity in spleen and bone marrow after multiple administration were slightly higher than those after administration of a single dose. Those in other tissues except thyroid gland, were similar to those after administration of a single dose. The remained radioactivity in the injection site at 10h after multiple administration was 33.65%, which was similar to that of single administration.
3. Until 96h after final administration of ¹²⁵I-EPOCH, urinary excretions of total. the TCA-precipitable and the immunoreactive radioactivity were 76.43%, 0.97%, 0.49%, respectively. Fecal excretion of total radioactivity was 3.83%, until 96h after final administration.

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The pharmacokinetics of quinotolas t sodium in rats, guinea pigs and dogs were studied after a single intravenous or oral dosing.
1. After intravenous dosing of 1mg/kg to rats, guinea pigs and dogs, the plasma concentration of quinotolast declined with respective terminal halflives of 1.8, 6.1, 10.4hr.
2. Total body clearance was 27.9, 6.8, 0.94ml/min/kg and the volume of distribution at steady state was 320, 1393 and 624ml, /kg in rats, guinea pigs and dogs respectively.
3. After oral dosing of 0.32 ?? 3.2mg/kg to rats, 1mg/kg to guinea pigs and 0.32 ?? 3.2mg/kg to dogs, the time to reach maximum plasma concentration was 5 ?? 20min, 2hr, 0.7 ?? 1.7hr and bioavailability was 0.55 ?? 0.64, 0.63, 0.55 ?? 0.85 respectively.
4. After oral dosing, the area under the plasma concentration-time curves in rats and dogs apeared to be proportional to dose over the range of 0.32 ?? 3.2mg/kg.
5. After oral dosing to rats, the area under the plasma concentration-time curves of quinotolast and hydroxy quinotolast were about the same, and it is considered that approximately 60% of quinotolast was metabolized to hydroxy quinotolast.

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The protein binding of quinotolast to the serum and plasma and its distribution in the blood cells were studied.
1. The blood to plasma consentration ratios of quinotolast were 0.59 ?? 0.60, 0.65 ?? 0.69, 0.65 ?? 0.69 and 0.72 ?? 0.76 respectively for human, rats, dogs and guinea pigs. The distribution extent of quinotolast in the blood cells were less than 20%, showing that quinotolast exists primarily in the plasma of these species in vitro.
2. The serum protein binding of quinotolast in vitro was 98.03 ?? 98.10, 96.49 ?? 96.70, 95.97 ?? 96.20 and 94.05 ?? 94.34% respectively for human, rats, dogs and guinea pigs for a concentration range of 0.1 ?? 10μg/ml. No difference between protein binding to human plasma and serum was found.
3. Quinotolast presumably is mainly bound to albumin of the human serum.
4. Protein binding of quinotolast to human serum in vitro was scarcely affected by prednisolone, procaterol or theophylline which might be used clinically with quinotolast, or by warfarin, diazepam or digitoxin which one mainly bound to albumin.
5. Protein binding of quinotolast to the human plasma in vivo was 98.45 ?? 98.71%. Since there was no difference between in vivo and in vitro binding, it is considered that the metabolites didn't affect the binding of quinotolast to the plasma protein.

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Loxoprofen is a 2-arylpropionic acid nonsteroidal anti-inflammatory drug (profen NSAID) with a cyclopentanone moiety. After absorption as unchanged form from gastrointestinal tract, the drug is transformed to the active metabolite, (2S, 1'R, 2'S)-trans-alcohol, which exerts pharmacological effects based on prostaglandin synthesis inhibition. The stereoselective determination method of the active metabolite was developed by combination of antibody-mediated extraction and diastereomeric amide derivatization for HPLC. Using the method, (2S, 1'R, 2'S)-trans-alcohol was found to be preferentially present in plasma among the possible eight monoalcohol enantiomers. The three stereoselective metabolic reactions, reduction of the cyclopentanone ring, conversion of cis-alcohol to trans-alcohol and chiral inversion of the propionic acid side chain, were favorable for the formation of the active metabolite. These stereoselective metabolism studies contributed to the development of this drug as a prodrug.
The mechanism of chiral inversion was studied by analysis of MS and NMR spectra of the rat urinary metabolite, tert-alcohol, after administration of 2-(2-isopropylindan-5-yl)propionic acid labeled with deuterium. Upon chiral inversion, deuterium atoms at the methyl position were retained but the methine deuterium was lost, contrary to the Wechetr's 2, 3-dehydro intermediate theory⁹⁾. Recently, many investigators have shown the results in conflict with 2, 3-dehydro intermediate mechanism. Nakamura et al¹¹⁾. proposed that the essential reaction in chiral inversion is the stereospecific CoA thioester formation of the R-enantiomers.
Since the activation of carboxylic acid to CoA thioester is also the fir st step for the amino acid conjugation, only the R-enantiomers was thought to yield amino acid conjugate in profen NSAID. This hypothesis was examined in dogs using 2-phenylpropionic acid (2-PPA) as a model compound. Unexpectedly, the 2-PPA glycine conjugate was produced from both enantiomers, and further the reverse chiral inversion (S to R) was observed in a simillar extent as the chiral inversion (R to S). The reverse chiral inversion was dependent on species and substrates employed, suggesting the presence of acyl CoA synthetases exhibting different stereoselectivity. The stereospecificity of glycine N-acyl transferase for the S-2-PPA CoA was presumed.

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The study of pharmacokinetics seeks to explain the time course of drug concentration in the body, while pharmacodynamics describes the drug effects once the drug has reached its site of action. The quantitative evaluation of drug action in vivo therefore requires the linkage of pharmacokinetics and pharmacodynamics. In addition, when the drug effect on the body is not directly measurable, for example with enzyme inhibition, the physiological consequences of this effect are often used as a measure of drug effect. Incorporation of what is known about the physiological regulation system into a physiological effect model can enhance not only the understanding of the pharmacodynamics of the drug, but also of the physiological process.
In the present study, we have investigated the effects of disease states on the pharmacokinetics and pharmacodynamics of various drugs such as propranolol, ajmaline, and natriuretic peptides. As we learn more about the effects of diseases, age, gender and other individual characteristics on the pharmacokinetics and pharmacodynamics of drugs, it will become possible to make drug therapy more effective and safer.

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This review shows the usefulness of electrophysiological methods on the analysis of drug permeation across the intestinal membrane. Mechanisms of the change in the membrane permeability by exo- or end-genus factors could be analyzed from the change in the electrical parameters of the membrane. The voltage-clamp method successfully presented the direct evidence on the existence of two different pathways for drug permeation in the jejunal epithelium. In addition, this method was thought to be useful to investigate the drug permeability in the stratum corneum. Finaly, the possibility was suggested for in vitro experiment to estimate in vivo drug absorption from the gastrointestinal tract by utlizing the cultured cell line, Caco-2 monolayer.

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