Drug Action In Disease States Research Articles

In Memoriam: Gerhard Levy, PharmD

In Memoriam: Gerhard Levy, PharmD

Kinetics of drug action in disease states: towards physiology-based pharmacodynamic (PBPD) models.

Gerhard Levy started his investigations on the “Kinetics of Drug Action in Disease States” in the fall of 1980. The objective of his research was to study inter-individual variation in pharmacodynamics. To this end, theoretical concepts and experimental approaches were introduced, which enabled assessment of the changes in pharmacodynamics per se, while excluding or accounting for the cofounding effects of concomitant changes in pharmacokinetics. These concepts were applied in several studies. The results, which were published in 45 papers in the years 1984–1994, showed considerable variation in pharmacodynamics. These initial studies on kinetics of drug action in disease states triggered further experimental research on the relations between pharmacokinetics and pharmacodynamics. Together with the concepts in Levy’s earlier publications “Kinetics of Pharmacologic Effects” (Clin Pharmacol Ther 7(3): 362–372, 1966) and “Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin” (Clin Pharmacol Ther 10(1): 22–35, 1969), they form a significant impulse to the development of physiology-based pharmacodynamic (PBPD) modeling as novel discipline in the pharmaceutical sciences. This paper reviews Levy’s research on the “Kinetics of Drug Action in Disease States”. Next it addresses the significance of his research for the evolution of PBPD modeling as a scientific discipline. PBPD models contain specific expressions to characterize in a strictly quantitative manner processes on the causal path between exposure (in terms of concentration at the target site) and the drug effect (in terms of the change in biological function). Pertinent processes on the causal path are: (1) target site distribution, (2) target binding and activation and (3) transduction and homeostatic feedback.

Kinetics of Drug Action in Disease States. XLIII: Potentiating Effect of l-Tryptophan on the Hypnotic Action of Phenobarbital and Ethanol in Rats

The essential amino acidl-tryptophan has been widely used as a sleeping aid because it can produce drowsiness and decrease sleep latency. Its concentrations in plasma and brain and its binding to plasma protein are markedly altered in hepatic encephalopathy and renal failure. The purpose of this investigation was to determine ifl-tryptophan can enhance the sensitivity of the central nervous system to the hypnotic actions of a barbiturate and an alcohol. Female rats weighing ∼200 g received an intravenous infusion ofl-tryptophan (0.8 or 0.08 mg/min) for 30 min and then an infusion of phenobarbital (0.824 mg/min) withl-tryptophan (0.8 or 0.08 mg min−1) until the onset of loss of righting reflex (LRR). Control animals received an infusion of saline solution for 30 min and then phenobarbital without the amino acid. Similar experiments were performed with ethanol (16.3 mg/min), with and withoutl-tryptophan (0.8 mg/min).L-Tryptophan infused alone at a rate of 3.8 mg/min for 84 min did not cause LRR. Administration ofl-tryptophan at a rate of 0.8 mg/min with phenobarbital was associated with statistically significant reductions in the total dose and concentrations of phenobarbital in serum, serum water, brain, and cerebrospinal fluid (CSF) at onset of LRR. The 0.08 mg/min infusion ofl-tryptophan had a less pronounced effect, with statistically significant reductions of phenobarbital concentrations at onset of LRR in brain and CSF.L-Tryptophan also significantly reduced the total dose and the concentrations of ethanol in serum, brain, and CSF required to produce LRR. It is concluded thatl-tryptophan can potentiate the central nervous system depressant effects of phenobarbital and ethanol.

Kinetics of Drug Action in Disease States. 45. Effect of Elevated Plasma Creatinine Concentrations on the Hypnotic Action of Phenobarbital in Normal Rats

Kinetics of Drug Action in Disease States. 45. Effect of Elevated Plasma Creatinine Concentrations on the Hypnotic Action of Phenobarbital in Normal Rats

Kinetics of Drug Action in Disease States. XLII. Effect of Repeated Blood Sampling on the Pharmacodynamics of Phenobarbital in Rats

Kinetics of Drug Action in Disease States. XLII. Effect of Repeated Blood Sampling on the Pharmacodynamics of Phenobarbital in Rats

Kinetics of Drug Action in Disease States. XXXVIII: Effect of Body Temperature on the Convulsant Activity of Pentylenetetrazol in Rats

The purpose of this investigation was to determine the effect of body temperature on the pharmacodynamics (convulsant activity) of pentylenetetrazol (PTZ). Rats received an iv infusion of PTZ until the onset of maximal seizures, at which time samples of cerebrospinal fluid (CSF), brain, and blood (for serum) were obtained for subsequent determination of PTZ concentrations by HPLC. The PTZ infusion caused a decrease in body temperature of ~4 <C within 20min and onset of seizures in ~40min. Compared with animals whose temperature was maintained in the normal range by heating pads, the hypothermic rats required significantly larger doses and higher serum, brain, and CSF concentrations of PTZ to produce seizures. Other rats received an injection of brewer's yeast to produce fever. Then, PTZ was infused 6, 12, or 24h later when body temperature was elevated by an average of 1.3, 1.1, or 0.4 <C, respectively. Compared with control rats, whose temperature was maintained in the normal range by heating pads, moderate hyperthermia had no significant effect on the dose and concentrations of PTZ required to produce maximum seizures. Pentylenetetrazol exemplifies a drug that can produce hypothermia which, in turn, reduces the sensitivity of rats to its pharmacologic action. Unlike the central nervous system (CNS) depressants phenobarbital and ethanol, whose pharmacologic activity in rats is enhanced at elevated body temperature, the activity of the CNS stimulant PTZ is apparently not altered by fever.

Kinetics of drug action in disease states. XL. Effect of the dialyzable component(s) of uremic blood on theophylline neurotoxicity in rats.

Kinetics of drug action in disease states. XL. Effect of the dialyzable component(s) of uremic blood on theophylline neurotoxicity in rats.

Kinetics of drug action in disease states. XXXIX. Effect of orally administered activated charcoal on the hypnotic activity of phenobarbital and the neurotoxicity of theophylline administered intravenously to rats with renal failure.

The central nervous system (CNS) sensitivity to the hypnotic (general anesthetic) action of phenobarbital and to the neurotoxic (convulsive) action of theophylline is greater in rats with acute renal failure than in normal animals, consistent with clinical observations. In the case of phenobarbital, this increased sensitivity can be produced in normal rats by infusion of a solution of the lyophilized dialysate of serum from rats with renal failure. It was hypothesized that the relevant constituent(s) of this dialysate may circulate between the blood and the intestinal lumen and that it (they) can be adsorbed by orally administered activated charcoal and thereby removed from the body. If so, treatment of renal failure rats with activated charcoal should partly reverse the increased CNS sensitivity to phenobarbital and to other drugs similarly affected. Accordingly, rats with renal failure produced by bilateral ligation of ureters were given an aqueous suspension of activated charcoal, about 1 g per kg body weight, orally every 8 hr for six doses. Uremic controls received equal volumes of water. About 2 hr after the last dose, the animals were infused i.v. with phenobarbital to onset of loss of righting reflex or with theophylline to onset of maximal seizures. In the phenobarbital study, charcoal treatment partly reversed the hypothermia associated with renal failure and caused a reduction of creatinine and total bilirubin concentrations in serum. The cerebrospinal fluid (CSF) concentration of phenobarbital at onset of loss of the righting reflex was significantly higher in charcoal treated rats than in their controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics of Drug Action in Disease States. XXXVI: Effect of Cyclosporine on the Pharmacodynamics and Pharmacokinetics of a Barbiturate (Heptabarbital) in Rats

Pretreatment with cyclosporine reportedly prolongs the effect of certain general anesthetics in humans and the sleeping time of mice after pentobarbital administration. This investigation was designed to determine the mechanism(s) of the cyclosporine–barbiturate interaction. Adult female Wistar rats received cyclosporine (50 mg/kg im) or saline solution daily for 3 days. On the third day, they were injected with heptabarbital (45 mg/kg iv). Other cyclosporine-treated and control groups were infused with heptabarbital until they lost their righting reflex. Treatment for 3 d with cyclosporine was associated with decreased rectal temperature, decreased magnesium concentrations in serum and CSF, increased serum creatinine and urea nitrogen concentrations, elevated serum aspartate aminotransferase activity and total bilirubin concentration, decreased serum total protein concentration, and increased hematocrit. These physiologic changes are consistent with the clinically observed hypomagnesemia, nephrotoxicity, and hepatotoxicity in patients treated with cyclosporine. Control rats slept for 90 ± 14 min (mean ± SD, n = 9) after heptabarbital injection, whereas cyclosporine-pretreated rats slept for 154 ± 22 min. Compared with controls, cyclosporine-pretreated rats awoke (after heptabarbital injection) and went to sleep (after heptabarbital infusion) with significantly lower barbiturate concentrations in serum and CSF. Pretreatment with a single 60-mg/kg im dose of cyclosporine 2 h before heptabarbital infusion caused no significant biochemical changes ~160 min later, except for elevated serum aspartate aminotransferase (which occurred also after injection of the surfactant-containing vehicle) and serum bilirubin. Again, heptabarbital concentrations at onset of sleep (loss of righting reflex) in serum, brain, and CSF of cyclosporine-treated rats were significantly lower than in saline-treated controls. Two or three days of pretreatment with cyclosporine (50 mg/kg/day, im) had no significant effect on the total clearance of the barbiturate. These results indicate that cyclosporine can prolong barbiturate-induced general anesthesia by a pharmacodynamic mechanism.

Kinetics of drug action in disease states. XXXI. Effect of experimental hyperthyroidism on the hypnotic activity of a benzodiazepine (oxazepam) in rats.

This investigation was designed to determine the effect of experimental hyperthyroidism on the hypnotic activity of a benzodiazepine and on the binding characteristics of the benzodiazepine receptor complex. Rats were made hyperthyroid by subcutaneous implantation of slow release pellets containing L-thyroxine. This treatment produced the characteristic symptoms of hyperthyroidism: increased serum thyroxine concentrations, increased heart weight and body temperature, and decreased serum protein concentrations. The hyperthyroid rats and a parallel group of normal animals (with drug-free pellets implanted subcutaneously) were slowly infused intravenously with oxazepam until they lost their righting reflex. The hyperthyroid rats required a significantly larger dose of the benzodiazepine and their total serum and cerebrospinal fluid concentrations of oxazepam (but not the serum concentration of free drug and the brain concentration) at the onset of loss of the righting reflex were modestly but statistically significantly lower than those of the normal rats. The receptor density and affinity for diazepam in hyperthyroid rats were not significantly different from those of the normal animals. Hyperthyroidism apparently affects the pharmacokinetics of oxazepam but has, at best, only a small effect on the pharmacodynamics (hypnotic activity) of the drug.

Pharmacodynamics of zoxazolamine and chlorzoxazone in rats.

Zoxazolamine is used for the pharmacologic assessment of possible changes in oxidative enzyme activity (paralysis time test) in rodents, whereas one of its metabolites, chlorzoxazone, is used clinically as a skeletal muscle relaxant. In this investigation, the pharmacodynamics of the two compounds were characterized in normal adult rats to determine their suitability for studies of the kinetics of drug action in disease states. Upon i.v. infusion 5 min beyond the onset of loss of the righting reflex (LRR) and concomitant blood sampling, serum concentrations of either drug were higher at the onset than at the offset of LRR, suggestive of a distribution disequilibrium. When zoxazolamine was infused at three different rates to onset of LRR, the pharmacologic end point was reached in 10 to 53 min. Drug concentrations in serum and brain at onset of LRR increased with increasing infusion rate, whereas drug concentrations in cerebrospinal fluid (CSF) were infusion rate independent and essentially identical to CSF concentrations at offset of LRR. Similar experiments (five infusion rates) with chlorzoxazone revealed drug infusion rate dependence even of CSF concentrations at the onset of LRR; only at very slow infusion rates (onset of effect in greater than or equal to 50 min) were onset concentrations in CSF essentially equal to offset concentrations. Neither drug produced measurable metabolite concentrations in the CSF. It is concluded that zoxazolamine but not chlorzoxazone distributes rapidly between CSF and the biophase, metabolites of either drug do not contribute measurably to the pharmacologic effect, and neither drug is subject to development of functional tolerance under the experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics of drug action in disease states. XXII. Effects of contraceptive steroids on the pharmacodynamics of ethanol in rats.

This investigation was designed to determine the effect of treatment with contraceptive steroids on the central nervous system depressant activity of ethanol. Adult female rats received oral doses of ethynyl estradiol (0.1 mg kg-1 day-1), ethynyl estradiol and norethindrone (0.1 and 10 mg kg-1 day-1), or vehicle only for 14 days. Ethanol was then infused slowly iv until the animals lost their righting reflex. The concentrations of ethanol at that time in serum and cerebrospinal fluid were statistically significantly higher in rats treated with the estrogen-progestin combination than in control animals. Ethanol concentrations in rats treated only with the estrogen were intermediate and did not differ significantly from control values. These results indicate that treatment with an estrogen-progestin combination is associated with a decreased sensitivity of the central nervous system to the hypnotic activity of ethanol. This evidence of a pharmacodynamic interaction between contraceptive steroids and ethanol in rats is consistent with a recent clinical report of significant contraceptive steroid-related improvement in tolerance to ethanol with no apparent effect on the pharmacokinetics of ethanol.

Kinetics of Drug Action in Disease States XI: Effect of Nicotine on the Pharmacodynamics and Pharmacokinetics of Phenobarbital and Ethanol in Rats

The purpose of this investigation was to determine if the reported prolongation of barbiturate–and ethanol-induced sleeping times by nicotine in rodents are pharmacodynamic or pharmacokinetic interactions. Adult female rats were pretreated with nicotine, either 0.5 or 1.5 mg/kg ip acutely or 0.5 mg/kg ip daily for 6 d, whereas control animals received saline solution. Phenobarbital or ethanol was infused intravenously at a slow rate until the rats lost their righting reflex. Acute pretreatment with nicotine reduced significantly the serum, brain, and cerebrospinal fluid (CSF) concentrations of phenobarbital and ethanol, respectively, at the onset of the loss of the righting reflex. Chronic pretreatment with nicotine had no such potentiating effects, indicative of rapid development of tolerance to nicotine. Neither acute nor chronic pretreatment with nicotine had any apparent effect on the elimination kinetics of phenobarbital or ethanol, on biochemical indices of hepatic integrity and renal function, or on the permeability of the blood–CSF barrier to protein. Nicotine, unlike morphine, did not increase the nociceptive threshold (tail squeeze) of rats under the experimental conditions. It is concluded that acute, but not chronic, pretreatment with nicotine increases the sensitivity of rats to the hypnotic effects of phenobarbital and ethanol, respectively. These interactions are entirely pharmacodynamic and have no apparent pharmacokinetic component.

Kinetics of Drug Action in Disease States XII: Effect of Experimental Liver Diseases on the Pharmacodynamics of Phenobarbital and Ethanol in Rats

This investigation was designed to determine if liver diseases can modify the pharmacodynamics of the central nervous system depressants phenobarbital and ethanol. Two experimental models of liver diseases in rats were used: extrahepatic cholestasis produced by bile duct ligation and hepatic necrosis induced by carbon tetrachloride administration. Phenobarbital (both models) or ethanol (cholestasis model only) was infused slowly intravenously until the rats lost their righting reflex. Drug concentrations in serum, brain, and cerebrospinal fluid at that time were determined in the diseased animals as well as in shamoperated or solvent‐treated controls. Phenobarbital concentrations at the onset of action were not significantly different between controls and either 5‐d or 12‐d cholestatic rats, except for total serum concentrations which were lower in the cholestatic groups due to reduced protein binding. Ethanol concentrations were slightly but statistically significantly lower in 12‐d cholestatic rats as compared with controls. Neither 5‐d nor 12‐d carbon tetrachloride‐induced hepatic dysfunction had any significant effect on phenobarbital concentrations at the onset of loss of righting reflex, except for a marginal decrease in the cerebrospinal fluid concentration of rats that had been treated for 5 d with the hepatotoxin. It was concluded that, under the experimental conditions, the hepatic diseases investigated did not have appreciable effects on the central nervous system response to the hypnotic action of phenobarbital and ethanol.

Kinetics of Drug Action in Disease States III: Effect of Pregnancy on the Relationship between Phenytoin Concentration and Antiseizure Activity in Rats

The purposes of this investigation were to determine the effect of pregnancy on the susceptibility of female rats to experimentally induced seizures and on the relationship between serum phenytoin concentration and antiseizure activity. Pregnant rats (on the 18th day of gestation) were more susceptible than nonpregnant female rats to seizures produced by maximal electroshock or by a body-weight-based dose of pentylenetetrazol. There was no apparent difference between pregnant (20th day of gestation) and non-pregnant rats in the relationship between seizure protection (percent of animals protected) and the serum concentration of total (free plus protein-bound) phenytoin. The relationship between concentration and effect was essentially the same 20min after an injection of phenytoin and 2h after the start of a constant-rate infusion preceded by a loading dose of the drug. Since the protein binding of phenytoin is appreciably decreased in late pregnancy, the serum concentration of free phenytoin required for seizure protection tended to be higher in pregnant than in nonpregnant rats. This may be due to the increased susceptibility of pregnant rats to seizure stimuli.