A priori prediction of tissue:plasma partition coefficients of drugs to facilitate the use of physiologically-based pharmacokinetic models in drug discovery.

Mechanism of anticonvulsant action of valproate.

Naltrexone is a long acting competitive antagonist at opioid receptors which blocks the subjective and objective responses produced by intravenous opioid challenge. It is suitable for oral administration, and has been studied as an adjunct for use in opioid addiction management programmes. In non-comparative clinical trials involving detoxified patients, oral naltrexone reduced heroin craving and between 23 and 62% of patients remained in treatment after 3 to 4 weeks. However, in two studies 32 to 58% of patients who continued in treatment were opioid-free between 6 and 12 months after stopping naltrexone. As might be expected studies involving highly motivated patients have shown this type of patient group to achieve greater treatment success rates during naltrexone therapy, and remain opioid-free longer than other groups of apparently less motivated patients. In addition, when naltrexone is combined with family support, psychotherapy and counselling, patients are more likely to remain opioid-free. Naltrexone produces a low incidence of side effects, with gastrointestinal effects being the most commonly reported symptoms. Thus, despite the overall high attrition rates from trials, in selected patient groups and in combination with appropriate support mechanisms and psychotherapy, naltrexone represents a useful adjunct for the maintenance of abstinence in the detoxified opioid addict.

Naltrexone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence.

Acyl glucuronide reactivity in perspective: biological consequences.

Acyl glucuronidation is the major metabolic conjugation reaction of most carboxylic acid drugs in mammals. The physiological consequences of this biotransformation have been investigated incompletely but include effects on drug metabolism, protein binding, distribution and clearance that impact upon pharmacological and toxicological outcomes. In marked contrast, the exceptional but widely disparate chemical reactivity of acyl glucuronides has attracted far greater attention. Specifically, the complex transacylation and glycation reactions with proteins have provoked much inconclusive debate over the safety of drugs metabolised to acyl glucuronides. It has been hypothesised that these covalent modifications could initiate idiosyncratic adverse drug reactions. However, despite a large body of in vitro data on the reactions of acyl glucuronides with protein, evidence for adduct formation from acyl glucuronides in vivo is limited and potentially ambiguous. The causal connection of protein adduction to adverse drug reactions remains uncertain. This review has assessed the intrinsic reactivity, metabolic stability and pharmacokinetic properties of acyl glucuronides in the context of physiological, pharmacological and toxicological perspectives. Although numerous experiments have characterised the reactions of acyl glucuronides with proteins, these might be attenuated substantially in vivo by rapid clearance of the conjugates. Consequently, to delineate a relationship between acyl glucuronide formation and toxicological phenomena, detailed pharmacokinetic analysis of systemic exposure to the acyl glucuronide should be undertaken adjacent to determining protein adduct concentrations in vivo. Further investigation is required to ascertain whether acyl glucuronide clearance is sufficient to prevent covalent modification of endogenous proteins and consequentially a potential immunological response.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/bdd.720

Acyl Glucuronides: The Good, The Bad and The Ugly

A specific gas chromatographic assay has been developed for measurement of valproic acid (VPA) and its major conjugated metabolites. In rats given single intravenous doses, the decline in blood concentration of VPA was dose-dependent and followed first-order kinetics only at the lowest dose. The time required for the maximum concentration of VPA, after completion of the brief distribution phase, to decline by 50% was 11.7, 41 and 125 min at doses of 15, 150 and 600 mg of NaVPA per kg, respectively. A secondary increase in drug concentration, abolished by exteriorization of the bile, was observed in all intact rats with all doses. Some 45 to 55% of the dose appeared in the bile in 5 hr as VPA glucuronide. Urinary excretion of VPA glucuronide in intact animals accounted for 23 and 51% of the 15 and 150 mg/kg doses, respectively. Tissue distribution studies in rats sacrificed 20 and 90 min after dosage with [14C] NaVPA (150 mg/kg) showed that the drug concentration was highest in blood, moderate in liver, kidney, heart and lung and low in brain, fat, testis and skeletal muscle. During this interval the drug concentration declined in all tissues, whereas the total conjugated metabolites in the small intestine increased from 7 to 28% of the administered dose. The large intestine contained 30 times as much free drug as conjugate. Reabsorption of free VPA, released by hydrolysis of conjugate in the large bowel, accounted for the secondary rise in concentration of VPA observed in blood after single doses. The major urinary metabolites, VPA-glucuronide and 2-n-propylgutaric acid, were identified by gas chromatography/chemical ionization mass spectrometry. Sodium VPA caused a dose-dependent stimulation of bile flow, the magnitude and duration of which closely followed the blood concentration of VPA.

Disposition of valproic acid in the rat: dose-dependent metabolism, distribution, enterohepatic recirculation and choleretic effect.

The pharmacokinetics, tissue distribution and metabolism of naltrexone were studied in male New Zealand White rabbits. After an i.v. bolus, the plasma half-life of naltrexone between 30 min and 3 hr was 55 +/- 5 min and 53 +/- 3 min for 1 and 5 mg/kg doses of naltrexone . HCl, respectively. The drug concentration in the semen reached a maximum value between 15 and 30 min after the injection. At 120 min, the semen/plasma drug concentration ratio was 14 and 11 for the 1 and 5 mg/kg doses, respectively. Three minutes after injection, 95% of the drug had left the plasma. After 5 min, the conjugate levels exceeded the free drug levels in the plasma suggesting rapid glucuronidation of the drug. The concentrations of naltrexone and 6-beta-naltrexol were measured in different tissues 90 min after injection. Most of the tissues had drug concentrations which exceeded the concurrent plasma concentration. The highest concentrations were observed in the submaxillary gland. Relatively high amounts of 6-beta-naltrexol were found in the brain, fat, spleen, heart, testis, kidney and urine. The principle urinary metabolite was the glucuronide of naltrexone. Minor metabolites identified in urine treated with Glusulase were 6-beta-naltrexol and N-dealkylated naltrexone.

The seminal excretion, plasma elimination, tissue distribution and metabolism of naltrexone in the rabbit.

Five adult cynomolgus monkeys (Macaca fascicularis) were each given doses of 15 and 150 mg/kg of sodium valproate on separate occasions through indwelling arterial or venous catheters. Timed samples of blood (0-1440 min) and urine were collected for measurement of free and conjugated valproic acid (VPA). In all animals a brief distribution (alpha) phase, complete by 10 to 15 min, was followed by a biphasic decline in concentration of the drug. The times required for the concentration of VPA in blood at 25 min to decline by 50% were 42.4 +/- 2.6 (S.E.) min and 94 +/- 7.5 (S.E.) min at the 15 and 150 mg/kg doses, respectively. The terminal half-lives (T 1/2) were 345 +/- 46 (S.E.) min and 428 +/- 56 (S.E.) min at the low and high dose, respectively. In contrast to our earlier studies in the rat, surgical exteriorization of the bile did not alter the elimination profile of VPA from the blood of the monkey. Only 3 to 7% of the administered dose of the drug appeared as conjugated VPA in the bile (c.f. 60% in the rat), thereby confirming that enterohepatic circulation of VPA was of minor importance in determining the pattern of elimination of the drug from blood in the monkey. Urinary excretion of conjugated VPA in intact and bile-exteriorized monkeys totaled 56 and 52% of the 15 mg/kg dose and 60 and 63% of the 150 mg/kg dose, respectively. In monkeys, as in rats, sodium valproate caused a dose-dependent, immediate choleretic reponse, the duration of which followed the blood concentration of the drug.

Nonlinear elimination and cholerteic effect of valproic acid in the monkey.

Dose dependent metabolism and enterohepatic recirculation of valproic acid in the rat.

A specific high-pressure liquid chromatographic assay was developed for the measurement of the narcotic antagonist drug, naltrexone. When 10 mg of naltrexone . HCl was added to the perfusate of the isolated perfused rat liver, the concentration of the drug in the perfusate declined rapidly with an apparent half-life of about 9 min. At 30 min 90% of the unchanged drug had been removed from the perfusate; the liver at this time retained 47% of the total radioactivity, of which only 75 represented unchanged drug. The bile at 30 min contained 28% of the total radioactivity and by 120 min this had risen to 70%. Initially naltrexone glucuronide was the principal metabolite in the bile. After 60 min N-dealkylated naltrexone glucuronide was the principal metabolite in bile. A marked increase in bile flow was noted immediately after the addition of the drug to the perfusate. The choleretic effect was attributed to the osmotic effect of the metabolites of naltrexone in the bile.

R M Rodgers

Papers

Disposition of valproic acid in the rat: dose-dependent metabolism, distribution, enterohepatic recirculation and choleretic effect.

The seminal excretion, plasma elimination, tissue distribution and metabolism of naltrexone in the rabbit.

Nonlinear elimination and cholerteic effect of valproic acid in the monkey.

Dose dependent metabolism and enterohepatic recirculation of valproic acid in the rat.

Metabolism and choleretic effect of naltrexone in the isolated perfused rat liver.