We investigated the plasma concentration profile, distribution, metabolism and excretion of radioactivity after a single intravenous administration of ¹²⁵I-YM866 in male rats.
1. After a single intravenous administration of ¹²⁵I-YM866, more than 50% of this drug rapidly formed two high molecular complexes with plasma proteins. The ratio of trichloroacetic acid (TCA)-precipitable radioactivity to total radioactivity in plasma decreased with time, suggesting that this drug is metabolized into low molecular weight metabolite or free ¹²⁵I. Immunoreactive YM866 concentrations decreased more rapidly than total or TCA-precipitable radioactivity.
2. After a single intravenous adminis tration of ¹²⁵I-YM866, radioactivity levels were highest in the plasma, followed by whole blood, liver, kidney, adrenal gland, spleen, lung, pituitary gland and thyroid. Radioactivity levels in these tissues were one-quarter or half of that in the plasma, and the level in the brain was much lower than in the plasma. Except for the uptake of the released ¹²⁵I by some specific tissues, the radioactivity in most tissues decreased rapidly. Although most of the radioactivity in tissues were precipitable with TCA at an early stage after administration, the ratio of TCA-precipitate to total radioacivity decreased rapidly with time.
3. After a single intr avenous administration of ¹²⁵I-YM866, 91.2% and 3.9% of the dosed radioactivity was excreted in urine and feces within 144 hr, respectively. Most of the radioactivity in urine was not precipitable with TCA and eluted in the gel filtration chromatographic (GFC) analysis at a low molecular region, suggesting that the radioactivity was excreted as low molecular weight materials
4. The concentration of ¹²⁵I-YM866 in plasma was higher than that of ¹²⁵I-tissue plasminogen activator (¹²⁵I-t-PA), probably because ¹²⁵I-YM866 was distributed less extensively to the liver than 125I-t-PA.

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We investigated the plasma concentration profile, distribution, metabolism and excreion of radioactivity after repeated intravenous administration of 0.3 mg/kg of ¹²⁵I-YM866 for 7 days to male rats. 1. After repeated dosing, plasma concentration-time curve profile of total and trichloroacetic acid (TCA)-precipitable radioactivity on the 7th day was closely similar to that after a single dose. In plasma, complexes of α₂-macroglobulin and α₂-plasmin inhibitor with ¹²⁵I-YM866, the unchanged YM866 and low molecular weight metabolites were observed by the gel filtration chromatographic (GFC) analysis after both single and multiple (7 days) the 7th administration.
2. Total radioactivity in tissues and corresponding tissue/plasma concentration ratios after the 7th repeated administration were closely similar to those after a single dose, except in the thyroid gland. Radioactivity distributed to the tissues rapidly disappeared from most of them. Tissue levels of radioactivity were little affected by repeated administration.
3. The excretion of radioactivity in the urine and feces showed little change throughout the period of repeated intravenous administration of ¹²⁵I-YM866. Within 120 hr after final dosing, 93.0% and 3.0% of the dosed radioactivity was excreted in urine and feces, respectively. Most radioactivity excreted in the urine was confirmed to be low molecular weight metabolites and/or free ¹²⁵I by GFC analysis.
4. These finding suggested that the metabolic fate of YM866 was little affected by repeated administration; no accumulation of radioactivity was observed.

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We investigated the feto-placental transfer and excretion into the milk after single intravenous administration of ¹²⁵I-YM866 to pregnant rats or nursing rats.
1. After administration of ¹²⁵I-YM866 to pregnant rats on day 14 of gestation, a little radioactivity was transferred to the fetus, and most of the distributed radioactivity was not precipitable with trichloroacetic acid (TCA). Therefore, the radioactivity in the fetus was confirmed to be low molecular weight metabolites and/or free ¹²⁵I.
2. After administration of ¹²⁵I-YM866 to pregnant rats on day 19 of gestation, transfer of radioactivity to the fetus was minimal as revealed by the whole-body autoradiograms.
3. After administration of ¹²⁵I-YM866 to nursing rats on day 14 after delivery, comparatively high radioactivity was transferred to the milk. But in the lactating rats, the plasma and tissue concentrations of radioactivity were less than 1/8 of that in the clotted milk in the stomach, suggesting that the absorption of radioactivity from the intestinal tract was low.

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Polaprezinc is a zinc complex of L-carnosine. Studies on the drug interaction of some antibiotics with polaprezinc in dogs were performed, because of the reported changes in the gastrointestinal absorption of some antibiotics in the presence of di- or tri-valent cations such as aluminium, ferrous and calcium ion.
The gastrointestinal absorption of norfloxacin was significantly reduced by coadministration with polaprezinc in dogs, but that of levofloxacin and sparfloxacin not affected. The C_max and AUC of tetracycline were slightly decreased by polaprezinc treatment. On the other hand, sucralfate, containing aluminium, significantly impaired the absorption of norfloxacin, levofloxacin and sparfloxacin. The effect of sucralfate on the absorption of tetracycline was greater than that of polaprezinc. Differeces between polaprezinc and sucralfate on the absorption of antibiotics may result from different ability of each metal ion for chelate formation with antibiotics.
In non-fasted dogs, polaprezinc did not affect the absorption of norfloxacin, levofloxacin and sparfloxacin. The interaction of norfloxacin with polaprezinc was markedly reduced by food. The obtained results indicated that the amount of zinc dissosiated from polaprezinc decreased by pH elevation in stomach due to food intake. Sucralfate severely impaired the absorption of norfloxacin, but slightly that oflevofloxacin and sparfloxacin.

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The metabolism of omeprazole, a selective inhibitor of H⁺, K⁺-ATPase, was studied after oral administration to male rats. In addition to already reported metabolites, 10 unconjugated and 6 conjugated metabolites were isolated from the urine by using TLC and HPLC. The structures of the isolated metabolites were determined by NMR, IR and mass spectrometry. Biotransformation pathways of omeprazole consisted of the oxidation and reduction of the sulfinyl (SO) group, N-oxidation of the pyridine ring, O-demethylation of both methoxy groups, oxidation of the pyridine-5-methyl moiety, aromatic hydroxylation at the 5-position of benzimidazole, and cleavage of the molecule into pyridine and benzimidazole moieties. There was also conjugation with mercapturic acid to carbon at the 2-position of benzimidazole as well as sulfonation and glucuronidation of the hydroxy groups. Based on the structures of the identified metabolites, the metabolic pathways of omeprazole appeared to be very complicated. The tentative metabolic pathways of omeprazole in the rat are presented and discussed.

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The absorption, distribution, metabolism, excretion, transfer into the fetus and milk of MC903 were investigated in rats after a single subcutaneous administration (2 μg/kg).
1. The level of radioactivity in the plasma reached a C_max at 1 hr, the reafter decreased with a t_1/2 (2-8 hr) of 2.1 hr and a t_1/2 (24-120 hr) of 2.4 days in male rats. Similar results were obtained in female rats. The linearity was observed in the dose range of 0.4 ?? 10 μg/kg.
2. The maximal levels of radioactivity, in examine d tissues of male rats, were reached at 1 hr. The elimination of radioactivity from tissues was slow.
3. The binding ability of MC903 to plasma protein was high in male rats. It was reversible in the in vitro conditions, but time-dependent increase of irreversible binding was observed in vivo.
4. Total recovery of radioactivity in male rats within 168 hr was 12.2, 68.5 and 1.3% in urine, feces and in expired air, respectively. Similar results were obtained in female rats. The entero-hepatic circulation of radioactivity was also observed.
5. The concentration of the unchanged drug in plasma was 961 μg/ml at 15 min after administration, and thereafter decreased rapidly. MC1080, RP7 and EB1057 were main metabolites of MC903. Trace of the unchanged drug was detected in pooled urine, feces and bile collected for 24 hr. Main metabolic species such as RU1 in urine, RF19 and MC1235 in feces, RB11, RB5 and RB7 in bile, were found. MC1080 and RU were detected in the liver and MC1080 and RK6 were found in the kidney.
6. The radioactivity in total fetuses or in the examined fetal tissues was lower than that found in maternal blood.
7. The profile of radioactivity in milk from lactating rats was similar to that in maternal plasma.

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The absorption, distribution, metabolism and excretion of MC903 were investigated in rats after a single dermal application in 5 μg/100 mg ointment/body using an occlusive dressing technique.
1. The radioactivity level in the plasma reached a C_max at 24 hr, and there after decreas ed with a t_1/2 (48-168 hr) of 2.9 days in male rats with an intact skin. In male rats with a stripped skin, the C_max and AUC(0-∞) were 23 and 6.9 times higher than those with an intact skin, respectively. In female rats with an intact skin, the t_1/2 and AUC(0-∞) were 4.5 and 4.1 times, respectively, higher than in male rats.
2. In male rats with an intact skin, the radioactivity levels in tissues examined gradually increased, and reached maximal levels between 24 and 96 hr. The elimination of radioactivity from tissues was slow. The whole body autoradiograms showed high levels of radioactivity in the application site of skin and in the gastro-intestinal content. The microautoradiogram of the skin showed that ³H-MC903 was absorbed mainly through the horny layer.
3. Total recovery of radioactivity in male rats with an intact skin within 168 hr was 2.0, 13.3 and 0.6% in urine, feces and in expired air, respectively. In male rats with a stripped skin, the excretion rates of radioactivity increased as compared with those of male rats with an intact skin. In female rats with an intact skin, the excretion rates of radioactivity increased as compared with those of male rats.
4. The unchanged drug was mainly detected in the application site of skin and in muscle layer under the skin.

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The absorption, distribution, metabolism, excretion and the effect of MC903 on hepatic drug metabolizing enzymes were investigated in male rats after multiple dermal application in 5 μg/100 mg ointment/body/day using an occlusive dressing technique or subcutaneous administration at the dose of 2 μg/kg/day.
1. After multiple dermal application, the radioactivity level in the plasma 24 hr after daily dosing reached a plateau level after the 5th dosing. The C_max after the 7th dosing was 8.3 times higher as compared with those after a single dosing, but the elimination of radioactivity was slow. Increase in total recovery of radioactivity in urine, feces and expired air was dependent on the number of dosing. Total recovery of radiaoctivity within 168 hr after the 7th dosing was 5.4, 30.7 and 1.9% in urine, feces and in expired air, respectively.
2. After multiple subcutaneous administration, the radioactivity level in the plasma 24 hr after daily dosing reached a plateau level after the 9th dosing. The radioactivity level in the plasma after the 21st dosing was higher than that after a single dosing. The excretion rates of radioactivity in urine, feces and expired air reached a plateau level after the 11th dosing. Total recovery of radioactivity within 168 hr after the 21st dosing was 16.6, 72.0 and 5.6%in urine, feces and in expired air, respectively.
3. After multiple subcutaneous administration, the radioactivity levels in examined tissues 24 hr after daily dosing gradually increased in parallel to number of dosings. The radioactivity levels in tissues after the 21st dosing decreased slowly as compared with those after a single dosing.
4. After multiple subcutaneous administration, the concentration of the unchanged drug in plasma was 605 pg/ml at 15 min after the 21st dosing, and thereafter rapidly decreased. MC1080 and RP7 were found as main metabolites. The ratio of the unchanged drug to its metabolites in pooled urine and feces collected for 24 hr after the 21st dosing was similar to that after a single dosing. Trace of the unchanged drug was found in the liver at 1 hr after the 21st dosing, and MC1080 and RU were found as main metabolites. The unchanged drug and main metabolites, MC1080 and RK6, were found in the kidney.
5. After multiple subcutaneous administration, the effect on hepatic drug metabolizing enzymes was slight and reversible.

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The absorption, metabolism and excretion of MC903 were investigated in male dogs after dermal application (100 μg/2 g ointment/body) using an occlusive dressing technique or subcutaneous administration (2 μg/kg).
1. The radioact ivity level in the plasma reached a C_max at 24 hr after dermal application, and thereafter decreased with a t_1/2 (48-168 hr) of 5.5 days. The radioactivity level in the plasma reached a C_max at 2 hr after subcutaneous administration, and thereafter decreased with a t_1/2 (4-8 hr) of 7.5 hr and a t_1/2 (24-168 hr)of 3.5 days.
2. Total recovery of radioactivity within 168 hr after dermal application was 0.6 and 5.3% in urine and feces, respectively. Total recovery of radio activity within 168 hr after subcutaneous administration was 5.9 and 78.8% in urine and feces, respectively.
3. The binding abilities of MC903 to plasma protein of dogs (in vitro and in vivo) and human (in vitro) were high and reversible. MC903 was mainly bound to albumin.
4. The concentration of the unchanged drug in plasma was C_max of 632 μg/ml at 1 hr after subcutaneous administration and thereafter decreased with a t_1/2 of 1.7 hr up to 8 hr. MC1080 was a main metabolite of MC903. Trace of the unchanged drug was detected in pooled urine and feces collected for 48 hr. DU1 and DU2 (glucuronide of MC1235) were main metabolites found in the urine. DF4 and MC1235 were those found in feces.

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Drug action is the result of interaction with target sites, for both desired (pharmacological) and undesired (toxic) actions, modulated by the transfer processes, the pharmacokinetic variables of absorption, distribution, metabolism and elimination, by which the drug enters and leaves the body. There exist in general better relationships between effect and internal exposure, i.e. target concentrations, most frequently related to plasma concentration, than with the external dose offered. Drug metabolism and pharmacokinetic studies have essential roles to play in all stages of the research and development process, ideally being involved from the pre-nomination phase in drug discovery through to post-marketing surveillance. There occurs far more inter and intraspecies variation, in animals and humans, in the factors influencing the nature and extent of internal exposure, than in the sensitivity of drug targets and this pharmacokinetic variability is the cause of major problems in drug development. The origins of this may be termed “pharmacokinetic defects” and include, inter alia, poor absorption, very short or very long half-life, enzyme induction and high first pass effect. Failure to take these into consideration can cause expensive delay and/or failure during development and make an approved drug vulnerable in the marketplace. It will be argued that the thoughtful inclusion of new feedback loops will improve decision making at various stages during drug development. These should be based on quality metabolic and pharmacokinetic data and exploit the opportunities which the new biology offers for predicting metabolic pathways, anticipating kinetic variability and understanding mechanisms of toxicity. Such improved decision making should contribute to enhanced time- and cost-efficiency of development and ultimately lead to safer, more easily used, drugs.

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