Phenobarbital distribution

Miscellaneous Pharmaceutical Processes. Solvent extraction is used for the preparation of many products that ate either isolated from naturally occurring materials or purified during synthesis. Among these are sulfa dmgs, methaqualone [72-44-6] phenobarbital [50-06-6] antihistamines, cortisone [53-06-5] estrogens and other hormones (qv), and reserpine [50-55-5] and alkaloids (qv). Common solvents for these appHcations are chloroform, isoamyl alcohol, diethyl ether, and methylene chloride. Distribution coefficient data for dmg species are important for the design of solvent extraction procedures. These can be determined with a laboratory continuous extraction system (AKUEVE) (244). 

S. Onishi, O. Yoshiki, Y, Nishimura, S. Itoh, and K. Itobe, Distribution of phenobarbital in serum, brain and other organs from pediatric patients, Dev. Pharmacol. Ther, 7, 153 (1984). 

Dispositional antagonism occurs when one drug alters the pharmacokinetics (absorption, distribution, biotransformation, or excretion) of a second drug so that less of the active compound reaches the target tissue. Tor example, phenobarbital induces the biotransformation of warfarin, reducing its anticoagulant activity... 

A, adult AED, antiepileptic drug C, child Co, combination therapy M, monotherapy PB, phenobarbital VD, volume of distribution. 

Diazepam is extremely lipophilic and quickly distributed into the brain, but redistributes rapidly into body fat, causing a very short duration of effect (0.25 to 0.5 hours). Therefore, a longer-acting anticonvulsant (e.g., phenytoin, phenobarbital) should be given immediately after the diazepam. The initial dose of diazepam can be repeated if the patient does not respond within 5 minutes. 

Aldous CN, Chetty CS, Desaiah D. 1983. Alterations in tissue distribution of chlordecone (Kepone) in the rat following phenobarbital or SKF-525A administration. J Toxicol Environ Health 11(3) 365-372. 

M14. Mulder, G. J., The effect of phenobarbital on the submicrosomal distribution of uridine diphosphate glucuronyltransferase from rat liver. Biochem. J. 117, 319-324 (1970). 

Phenobarbital is effective orally and is distributed widely throughout the body. It is metabolized by microsomal drug-metabolizing enzymes, but up to 50% of the parent drug is excreted unchanged by the kidneys. Primidone is metabolized to phenobarbital and phenyl-ethylmalonamide. The latter metabolite has anticonvulsant activity, but most of the anticonvulsant efficacy of primidone is due to the phenobarbital that is produced. 

Pharmacokinetics PO route onset 20-60 min, peak N/A, duration 6-8 hr. Well absorbed after PO administration. Widely distributed. Metabolized in liver to active metabolite, a form of phenobarbital. Minimally excreted in urine. Removed by hemodialysis. Half-life 34 hr. 

Examples of drugs with large volumes of distribution (> 5 L/kg) include antidepressants, antipsychotics, antimalarials, opioids, propranolol, and verapamil. Drugs with a relatively small (< 1 L/kg) include salicylate, ethanol, phenobarbital,... 

Changes in plasma pH may also affect the distribution of toxic compounds by altering the proportion of the substance in the nonionized form, which will cause movement of the compound into or out of tissues. This may be of particular importance in the treatment of salicylate poisoning (see chap. 7) and barbiturate poisoning, for instance. Thus, the distribution of phenobarbital, a weak acid (pKa 7.2), shifts between the brain and other tissues and the plasma, with changes in plasma pH (Fig. 3.22). Consequently, the depth of anesthesia varies depending on the amount of phenobarbital in the brain. Alkalosis, which increases plasma pH, causes plasma phenobarbital to become more ionized, alters the equilibrium between plasma and brain, and causes phenobarbital to diffuse back into the plasma (Fig. 3.22). Acidosis will cause the opposite shift in distribution. Administration of bicarbonate is therefore used to treat overdoses of phenobarbital. This treatment will also cause alkaline diuresis and therefore facilitate excretion of phenobarbital into the urine (see below). 

Barbiturates such as phenobarbital are weak acids. The toxicity of the barbiturate is mainly the result of the effects on the central nervous system. Only the nonionized form of the drug will distribute into the central nervous system. The proportion ionized will depend on the pKa and the pH of the blood. By increasing the pH of the blood using sodium bicarbonate administration to the poisoned patient, ionization of the barbiturate will be increased and distribution to tissues such as the brain will be decreased. Urinary excretion of the barbiturate will also be increased because the urinary pH will be increased. 

The tissue distributions of [l- C]- and [2,3- 4C]aciy lonitrile (40 mg/kg) were compared in Wistar rats after intraperitoneal and oral administration (Sapota, 1982). The relative distributions of the two labelled forms were very similar and the principal locations of C were erythrocytes, liver and kidney. After oral administration, the rate of elimination from tissues was slower for [cyano- C -than for [l,2-vz v/- 4C]acrylonitrile. After gavage administration of 46 mg/kg bw [2-i4C]acrylonitrile to Fischer 344 rats, radioactivity was well absorbed from the gastrointestinal tract and distributed to all major tissues 24 h after dosing. The highest levels were found in the forestomach, blood and urinary bladder. Prior treatment of rats with phenobarbital had little effect on the pattern of distribution and excretion of 4C, but the CYP inhibitor SKF-525A caused marked changes, with less excretion (less than 40% in urine in 24 h compared with over 60% in... 

Phenobarbital is utilized as a daytime sedative and anticonvulsant. It also induces several cytochrome P450 isozymes. Compared to other barbiturates, phenobarbital has a low oil/water partition coefficient, which results in slow distribution into the brain. It is available for oral, intravenous, or intramuscular administration. Doses for epileptic patients range from 60 to 200 mg per day. After a single oral dose of 30 mg, peak serum concentrations averaged 0.7 mg/L (n = 3). Repeated doses over a period of 7 days resulted in an average peak concentration of 8.1 mg/L.6 Chronic administration of 200 mg per day as anticonvulsant medication resulted in an average blood concentration of 29 mg/L (range = 16 to 48 mg/L).8... 

Pentobarbital is 65% plasma protein bound with a volume of distribution of 0.5 to 1.0 L/kg.6 After intravenous administration, estimates of the plasma half-life have averaged between 20 and 30 h. Amobarbital is similar to pentobarbital in the degree of plasma protein binding (59%) with a slightly larger volume of distribution (0.9 to 1.4 L/kg). The plasma half-life, however, is dose dependent, with a range of 15 to 40 h.6 Phenobarbital is approximately 50% plasma protein bound... 

Although hemodialysis is effective in removing phenobarbital/ methanol/ and other low molecular weight compounds that have a relatively small distribution volume and are not extensively... 

Painter, M.J. Pippenger, C.E. Wasterlein, C. Barmada, M. Pitlick, W. Carter, G. Aberin, S. Phenobarbital and phenytoin in neonatal seizures Metabolism and tissue distribution. Neurology 1981, 31, 1107-1112. 

Phenobarbital is absorbed rapidly and well after oral administration to horses, with bioavailability approaching 100% (Ravis et al 1987). It is distributed widely into the tissues but, because of its lower lipid solubility, does not distribute into the CNS as rapidly as other barbiturates. After i.v. administration, it may take 15-20 min before therapeutic concentrations of phenobarbital are reached in the CNS. Phenobarbital primarily undergoes hepatic metabolism and only 25% is excreted as unchanged drug. The half-lives reported in horses, around 18-24 h (Duran et al 1987, Knox et al 1982, Ravis et al 1987) and 12 h in foals (Spear et al 1984), are substantially shorter than in other species, meaning that steady-state concentrations can be achieved more rapidly. 

Estimates of the apparent volume distribution for phenobarbital vary nearly twofold... 

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