Pentobarbital metabolism

Dactylyne, a marine natural product that is an inhibitor of pentobarbital metabolism. 

Misra PS, Lefevre A, Ishii H, Rubin E, Lieber CS. Increase of ethanol, meprobamate and pentobarbital metabolism after chronic edianol administration in man and in rats. Am J Med... 

Two examples of alkynes among thousands that have a biosynthetic origin are capil-lin, an antifungal agent, and dactylyne, a marine natmal product that is an inhibitor of pentobarbital metabolism. Ethinyl estradiol is a synthetic alkyne whose estrogen-like properties have found use in oral contraceptives. 

Ueki, M., Mies, G. and Hossmann, K. A. Effect of alpha-chloralose, halothane, pentobarbital and nitrous oxide anesthesia on metabolic coupling in somatosensory cortex of rat. Acta Anaesthesiol. Scand. 36 318-322,1992. 

Choi, I. Y., Lei, H. and Gruetter, R. Effect of deep pentobarbital anesthesia on neurotransmitter metabolism in vivo on the correlation of total glucose consumption with glutama-tergic action. /. Cereb. Blood Flow Metab. 22 1343-1351, 2002. 

Some have suggested that the maintenance infusion rate should be adjusted as follows (1) if no metabolic enzyme inducers are present, the continuous infusion rate is 1 mg/kg/hour (2) if one or more inducers are present (e.g., phenobarbital, phenytoin), the rate is 2 mg/kg/hour and (3) if inducers and pentobarbital coma are present, the rate is 4 mg/kg/hour. 

Ueda S, Yamaoka K and Nakagawa T (1999) Effect of Pentobarbital Anaesthesia on Intestinal Absorption and Hepatic First-Pass Metabolism of Oxacillin in Rats, Evaluated by Portal-Systemic Concentration Difference. J Pharm Pharmacol 51 pp 585-589. 

An alternative process that can lead to the termination or alteration of biologic activity is metabolism. In general, lipophilic xenobiotics are transformed to more polar and hence more readily excreted products. The role that metabolism plays in the inactivation of lipid-soluble drugs can be quite dramatic. For example, lipophilic barbiturates such as thiopental and pentobarbital would have extremely long half-lives if it were not for their metabolic conversion to more water-soluble compounds. 

Two mechanisms help protect the fetus from drugs in the maternal circulation (1) The placenta itself plays a role both as a semipermeable barrier and as a site of metabolism of some drugs passing through it. Several different types of aromatic oxidation reactions (eg, hydroxylation, /V-dealkylation, demethylation) have been shown to occur in placental tissue. Pentobarbital is oxidized in this way. Conversely, it is possible that the metabolic capacity of the placenta may lead to creation of toxic metabolites, and the placenta may therefore augment toxicity (eg, ethanol, benzpyrenes). (2) Drugs that have crossed the placenta enter the fetal circulation via the umbilical vein. 

Pentobarbital has a half-life in the blood plasma of 80 years. In fact, it is metabolized in 4 to 6 hours. 

Although in some animals starvation appears to have effects similar to those of protein deficiency, this is not necessarily the case. For example, in the mouse, monooxygenation is decreased but reduction of p-nitrobenzoic acid is unaffected. In male rats, hexobarbital and pentobarbital hydroxylation as well as aminopyrine A-demethylation are decreased, but aniline hydroxylation is increased. All of these activities are stimulated in the female. Water deprivation in gerbils causes an increase in P450 and a concomitant increase in hexobarbital metabolism, which is reflected in a shorter sleeping time. 

In addition, the sleep-producing action of barbiturates is used to relax and partially anesthetize patients before some surgical procedures. Before some major brain surgeries, barbiturates (usually pentobarbital or thiopental) are used to temporarily induce coma in an effort to protect the brain these drugs can reduce the metabolic rate of brain tissue and control cerebral blood flow. 

Figure 3 Enzyme induction of alprenolol metabolism following pentobarbital treatment produces minimal changes in events in plasma following intravenous administration of alprenolol 5 mg to subjects ( before, during pentobarbital) but a marked lowering of the plasma concentrations following oral administration of alprenolol 200 mg (o before, A during pentobarbital). Source From Ref. 7.

Nakashima K., Todd M. M., and Warner D. S. (1995) The relation between cerebral metabolic rate and ischemic depolarization. A comparison of the effects of hypothermia, pentobarbital, and isoflurane. Anesthesiology 82, 1199-1208. 

Jaeger RJ, Murphy SD. 1973. Duration of action distribution and metabolism of pentobarbital or hexobarbital after 1, 1-dichloroethylene, corticosterone or acrolein. Fed Proc 32(3 Part 1) 320. 

Being one of the long-time standards in basic psychopharmacology, there are few major variants to the procedure apart from the kind of barbiturate employed. Several barbiturates undergo clear hepatic metabolism, for example pentobarbital and phenobarbital, thereby confounding interpretations because of pharmacokinetic and metabolic factors. Indeed, one modification of the method has been specifically employed to estimate enzyme induction in the liver as indicated by more rapid barbiturate metabolism. Animals given a pre-exposure to a test substance are then exposed to a standard dose of phenobarbital (80 mg/kg i.p.) 24 hours later and assessed for sleep duration. The presence or absence of a decrease in sleep duration is taken as an index of the hepatic enzyme induction produced by the test substance (Kushikata et al. 2003). 

Remmer H (1972) Induction of drug metabolizing enzyme system in the liver. Eur J Clin Pharmacol 5 116-136 Simon P, Chermat R, Doare L et al. (1992) Interactions im-prevues de divers psychotropes avec les effets du barbital et du pentobarbital chez la souris. J Pharmacol 13 241-252... 

Metabolic blood parameters are assayed in anesthetized male rats using a modified method of glucose clamp studies in rodents (Terrettaz and Jeanrenaud 1983). Four to 6 rats per group (vehicle control and one dose of the candidate compound) are used. Rats are anesthetized with an intraperitoneal injection of pentobarbital sodium (60 mg/kg), tracheotomized, and one jugular vein per rat is cannulated for intravenous infusion the other vein is prepared for collection of blood samples. Anesthesia is maintained for up to 7 hours by subcutaneous infusion of pentobarbital sodium (adjusted to the anesthetic depth of the individual animal about 24 mg/kg/h). Body temperature is monitored with a rectal probe thermometer, and temperature is maintained at 37 °C by means of a heated surgical table. Blood samples for glucose analysis (10 il) are obtained from the tip of the tail every 15 minutes, and for lactate analysis (20 p.1) every... 

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