To determine the contribution of the mdr1a gene product to digoxin pharmacokinetics, we constructed a physiologically based pharmacokinetic model for digoxin in mdr1a (-/-) and mdr1a (+/+) mice. After intravenous administration, total body clearance and tissue-to-plasma concentration ratios for muscle and heart were decreased in mdr1a (-/-) mice as compared with mdr1a (+/+) mice, and in particular, the digoxin concentration in the brain was 68-fold higher than that in mdr1a (+/+) mice at 12 h. On the other hand, mdr1a gene disruption did not change the contributions of renal and bile clearances to total clearance, the plasma protein binding, or the blood-to-plasma partition coefficient. Brain concentration-time profiles in mdr1a (+/+) and mdr1a (-/-) mice showed a different pattern from those in plasma and other tissues, indicating digoxin accumulation in the brain tissue. Because there was no difference in the uptake or release of digoxin by brain tissue slices from the two types of mice, we assumed the brain tissue compartment to consist of two parts (a well-stirred part with influx and efflux clearance and an accumulative part). Simulation with this model gave excellent agreement with observation when active efflux clearance across the blood-brain barrier was assumed to be zero in mdr1a (-/-) mice. The observations in other tissues in both types of mice were also well simulated.

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Inhibitory activities against angiotensin I-converting enzyme (ACE) of enzymatic hydrolysates of porcine skeletal muscle proteins were investigated. Myosin B, myosin, actin, tropomyosin, troponin and water-soluble proteins extracted from pork loin were digested by eight kinds of proteases, including pepsin, α-chymotrypsin, and trypsin. After digestion, hydrolysates produced from all proteins showed ACE inhibitory activities, and the peptic hydrolysate showed the strongest activity. In the case of myosin B, the molar concentration of peptic hydrolysate required to inhibit 50% of the activity increased gradually as digestion proceeded. The hydrolysates produced by sequential digestion with pepsin and α-chymotrypsin, pepsin and trypsin or pepsin and pancreatin showed weaker activities than those by pepsin alone, suggesting that ACE inhibitory peptides from peptic digestion might lose their active sequences after digestion by the second protease. However, the hydrolysates produced by sequential digestion showed stronger activities than those by α-chymotrypsin, trypsin or pancreatin alone. These results suggested that the hydrolysates of porcine meat were able to show ACE inhibitory activity, even if they were digested in vivo, and that pork might be a useful source of physiologically functional factors.