Inhibition Of Hepatic Drug-metabolizing Enzymes Research Articles

DRUG-METABOLIZING ENZYMES AND PRAZIQUANTEL BIOAVAILABILITY IN MICE HARBORING SCHISTOSOMA MANSONI ISOLATES OF DIFFERENT DRUG SUSCEPTIBILITIES

The level of drug-metabolizing enzymes (cytochrome P450 [CYP450] and cytochrome b5 [cyt b5]) and the bioavailability of praziquantel (PZQ) were investigated in batches of mice infected with Schistosoma mansoni displaying either a decreased susceptibility to PZQ ("EE2" and "BANL"-isolates), or a normal susceptibility to the drug ("CD" isolate). Each batch was divided into 2 groups. The first group was further subdivided into 5 subgroups. Subgroups 1 to 4 were treated 7 wk postinfection (PI) with oral PZQ at 25, 50, 100, and 200 mg/kg for 5 consecutive days, whereas the fifth subgroup was administered the vehicle only as control. Animals were perfused 9 wk PI, and worms were counted to estimate PZQ ED50. CYP450 and cyt b5 were examined in hepatic microsomes of infected untreated mice and of infected mice treated with 25 and 200 mg/ kg PZQ. The second group was given PZQ 7 wk PI and was further subdivided into 11 subgroups, killed at 2, 5, 15, 30, 60, 90, 120, 150, 180, 240, and 360 min postdosing to study pharmacokinetic parameters of PZQ. Mice harboring S. mansoni isolates having higher PZQ ED50 (170.3 mg/kg for EE2 and 249.9 mg/kg for BANL vs. 82.96 mg/kg for CD) had higher levels of CYP450 and cyt b5, a PZQ Cmax decreased by 19-30% and area under the serum concentration-time curve0-6 hr decreased by 57-74%. Data suggest that S. mansoni isolates that are less sensitive to PZQ induce a lower inhibition of hepatic drug-metabolizing enzymes, with a consequently higher metabolic transformation of PZQ.

Effects of subacutely administered saiboku-to, an oriental herbal medicine, on pharmacodynamics and pharmacokinetics of diazepam in rodents

Subacute treatment with saiboku-to (2000 mg/kg, p.o., once a day) for 7 days induced an anxiolytic-like effect in rats. It did not, however, produce any other effects, such as sedative and hypnotic effects, anticonvulsive and muscle relaxant effects except for anxiolytic effect observed in diazepam-injected rats or mice. Diazepam (1.0 mg/kg, s.c.) induced anxiolytic-like effect was enhanced in saiboku-to treated rats as an additional effect of that induced by saiboku-to. To elucidate whether the enhancement of the anxiolytic-like effect following combined administration of diazepam and saiboku-to is due to the inhibition of hepatic drug-metabolizing enzymes, the pharmacokinetics of diazepam were further investigated in saiboku-to treated rats. The pharmacokinetic studies clearly demonstrated that subacute treatment with saiboku-to did not affect plasma concentration and protein binding rate of diazepam, and the activities of hepatic drug-metabolizing enzymes related to diazepam metabolism. These results, taken together, suggest that the enhancement of diazepam-induced anxiolytic-like effect observed in saiboku-to-treated rats is not due to an inhibition of diazepam metabolism.

Inhibition of hepatic drug-metabolizing enzymes by arachidonic acid.

1. The effects of arachidonic acid on hepatic drug-metabolizing enzymes was investigated in male ICR-Swiss mice. 2. A single administration of arachidonic acid, 100 mg/kg i.p., doubled the hexobarbital sleeping time. Arachidonic acid in vitro gave a type I binding spectrum with hepatic microsomes; it inhibited the metabolism of hexobarbital and of ethylmorphine, two type I binding drugs, but not that of aniline, a type II binding drug; the inhibition of hexobarbital metabolism by arachidonic acid was competitive. 3. Repeated administration of arachidonic acid up to a total dose of 1000 mg/kg i.p., either in the course of 5 hours, or in the course of 5 days, decreased microsomal cytochrome P-450 levels and NADPH-cytochrome c reductase activity. 4. It is concluded that the administration of arachidonic acid may impair drug metabolism in two ways, mainly, by competitively inhibiting the activity of drug-metabolizing enzymes, and secondarily, by decreasing the hepatic concentration of these enzymes.

A study of the nature of pilocarpine inhibition of hepatic drug-metabolizing enzymes

A study of the nature of pilocarpine inhibition of hepatic drug-metabolizing enzymes

Inhibition of hepatic drug-metabolizing enzymes by thiophosphate insecticides and its drug toxicological implications

Thiophosphate insecticides—fenitrothion, diazinon and methylparathion—inhibit hepatic drug-metabolizing enzyme activity, which was assayed using aminopyrine and aniline as substrates. About 50 per cent inhibition was noted 4 hr after the injection of 25 mg/kg of fenitrothion into mice. The addition of thiophosphates to a microsomal drug-metabolizing enzyme system in vitro also produced an effective inhibition: IC 50 was ca 10 −5 M for fenitrothion. DDVP and an oxygenated metabolite of fenitrothion did not show any inhibiting effect either in vitro or in vivo. The inhibition in vitro was competitive, while the kinetics of inhibition in vivo appeared to be noncompetitive. Drug metabolism by a rat liver preparation was also inhibited by thiophosphate in vitro, but treatment of male rats in vivo resulted in little inhibition. The responses of female rats were similar to those of mice. The administration of fenitrothion to mice prolonged the hexobarbital sleeping time and suppressed the oxidative metabolism of parathion in liver preparations.

Effect of pyrithioxine on the histo-hematic baarriers.

Pyrithioxine (pyridoxine 5-disulfide) increased the pentobarbital-induced sleeping time in mice. This potentiation was divided into two phases ; one appeared immediately after the administration of pyrithioxine and reached a maximum within 20 min. The other appeared 8-10 hr later and corresponded to the inhibition of hepatic drug-metabolizing enzymes. When the potentiation without relation to the inhibition of hepatic drug-metabolizing enzymes occurred, the pentobarbital concentration increased in the brain and liver, but was unchanged in the serum. Pyrithioxine stimulated the transport of 14C-labeled fatty acids, glucose, amino acids, acetic acid, and inulin into the brain and liver, same as pentobarbital. Since [Na++K+]-ATPase, K+-phosphatase, and [Mg2++Ca2+]-ATPase activities were not influenced by pyrithioxine, this stimulation was not dependent on the increase of active transport, but depended on the increase of passive transport. However, the uptake of radioiodinated human serum albumin into the brain and liver of mice and the water content of these tissues were not affected by pyrithioxine treatment. The brain was not stained by Trypan Blue in pyrithioxine-treated and in control mice, but the liver, kidneys, intestines, skin, abdominal wall, and tail were stained deeper in pyrithioxine-treated mice. Increase in radioactivity from octanoate-1-14C was detected only in the free fatty acid fraction in the brain, but the radioactivity in the liver increased in the free fatty acid and the triglyceride fractions. This shows that pyrithioxine affects not only the histo-hematic barrier but also the fatty acid metabolism in the liver. Brain pentobarbital concentration at the time of awakening was lower in pyrithioxine-treated mice than the control. This result suggests that pyrithioxine increases the susceptibility of central nervous system to barbiturates. In addition, increased uptake of 45Ca in the brain indicates the disturbance of ion transport regulation which is necessary to preserve the central nervous excitability. These results suggest that pyrithioxine increases the pentobarbital sleeping time by three mechanisms of (1) inhibition of hepatic drug-metabolizing enzymes, (2) increase in brain pentobarbital concentration, and (3) decrease of excitability of the central nervous system.