An integrated approach to the pharmacokinetic analysis of drug absorption

A systematic approach to the estimation of bioavailability using both model-independent and pharmacokinetic techniques is introduced. The methods of Kwan-Till and Wagner-Nelson or Loo-Riegelman are integrated such that one is able to check many of the assumptions inherent in these techniques and make appropriate adjustments for apparent deviations. The proposed integrated method makes use of all available data (both plasma and urine) and leads to a better understanding of the absorption, distribution, metabolism, and excretion of the drug being studied.     

An integrated pharmacoeconomic approach to antimicrobial formulary decision-making.

PURPOSE: The utility of a novel interdisciplinary approach to antimicrobial formulary decision-making was studied. METHODS: Pseudomonas aeruginosa minimum inhibitory concentration (MIC) distribution data for cefepime and ceftazidime were retrieved from nonrepeat isolates obtained from November 2002 to October 2003. Unbound drug exposures were simulated for 5000 patients using the Monte Carlo method. Weighted target attainment rates (TARs) were calculated for cefepime and ceftazidime 1 g every 8 hours and 1 g every 12 hours (infused over 0.5, 2, and 4 hours), using three representative pharmacodynamic targets (percentage of time above the MIC of 67%, 100%, and 400%). RESULTS: MIC data for 1230 nonrepeat P. aeruginosa were analyzed. The MIC at which 90% of the P. aeruginosa isolates were inhibited was 16 and 32 mg/L for cefepime and ceftazidime, respectively. Drug acquisition cost was the highest with cefepime 1 g given every 8 hours (37.56 dollars/day), followed by cefepime 1 g every 12 hours (25.04 dollars/day) and ceftazidime 1 g every 8 hours (22.26 dollars/day). When infused over 0.5 hour, the highest TAR was achieved with cefepime 1 g every 8 hours (82%), followed by ceftazidime 1 g every 8 hours (77%) and cefepime 1 g every 12 hours (66%); ceftazidime 1 g every 8 hours was 70% more cost-effective than cefepime 1 g every 8 hours. Cefepime 1 g every 12 hours, infused over 4 hours, increased the TAR to 89% and was similar in cost-effectiveness to ceftazidime 1 g every 8 hours infused over 0.5 hour. CONCLUSION: An integrated pharmacoeconomic approach to antimicrobial formulary decision-making addressed local resistance patterns, population pharmacokinetics, pharmacodynamics, dosing regimens, and drug acquisition costs. This method appeared to be more realistic and objective than the conventional approach of considering only drug acquisition costs, especially for agents in a similar structural or functional class.     

An approach to deposition and clearance measurements in human airways.

By using the aerosol bolus inhalation technique, aerosol particles can be delivered into the airways of the human respiratory tract. For that purpose the aerosol bolus is injected near the end of a clean air inhalation. It could be shown experimentally and theoretically that the particles were only deposited in the airways. Radioactive labeled particles were deposited with this technique and clearance from the airways was determined. It could be shown that the mucociliary clearance from the airways was particle size dependent. The clearance efficiency from the airways increased with increasing particle size.     

The use of single-sample clearance estimates to probe hepatic drug metabolism in rats. IV. A model for possible application to phenotyping xenobiotic influences on human drug metabolism

1. Conditions were examined under which estimates of drug clearance made from a single measurement of plasma concentration effectively represented multi-sample estimates of clearance for carbamazepine, quinidine, and paracetamol. When plasma concentrations were measured at various post-dose times, both individual and mean values of single-sample clearance estimates (CL) corresponded closely to multi-sample clearance estimates. Best post-dose sampling times were: carbamazepine, 3 h; quinidine, 10 h; and paracetamol, 6 h. 2. Single sample clearance estimates, CL, were calculated for seven drugs employed as probes of hepatic drug-metabolizing activity in rats. Valproic acid was investigated as a probe of microsomal and peroxisomal oxidases; antipyrine, theophylline, ethosuximide, carbamazepine and quinidine as probes of hepatic mixed-function oxidases (MFO), and paracetamol as a probe for UDP-glucuronosyltransferase activity. 3. A clearance index (CI, namely, probe CL after xenobiotic pretreatment divided by control probe CL) was calculated for each probe. Eight pretreatments were used: phenobarbital (PB), beta-naphthoflavone (beta NF), polychlorinated biphenyls (PCB), rifampin, pregnenolone-16 alpha-carbonitrile (PCN), clofibric acid, cimetidine, and piperonyl butoxide. The effect of each xenobiotic pretreatment on all probe CL values was consolidated and plotted as the logarithm of the CI, and a distinct pattern or handprint evolved for each pretreatment. 4. We conclude that the use of multiple single-sample probes of hepatic MFO activity can be useful in structuring handprints to characterize xenobiotic-mediated effects on hepatic MFO. This minimally invasive in vivo approach may have application in investigating and possibly phenotyping MFO activity in human subpopulations that are subject to sustained exposure to particular xenobiotics.     

An integrated approach for the evaluation of psychotropic drug in man

Following an integrated approach based on the contemporary recording of drug plasma levels, central (CNS) and peripheral responses and performance tests, the effects of two different amphetamine formulations were evaluated in healthy volunteers.Interesting relationships were observed between amphetamine initial rate of entry into the blood stream and both incidence of side effects (S.E.) and rise in arterial blood pressure. Minimal thresholds for CNS (5 ng/ml) and peripheral (20 ng/ml) effects could also be determined. It appeared also that the personality of the subject may have some bearing on both incidence of side effects and performance. The described methodology seems valuable in valuating psychotropic drug effects in man through a comprehensive integrated approach.     

The use of single sample clearance estimates to probe hepatic drug metabolism: handprinting the influence of phenobarbitone on human hepatic drug metabolism.

1. Single sample clearance estimates, CL, were calculated for seven drugs employed as probes of human hepatic drug-metabolizing enzymes. Clearance estimates were calculated in healthy young adult male volunteers either taking no pretreatment, or taking phenobarbitone (PB) 100 mg nightly for 3 nights. This intermittent regimen (3 nights on, followed by 4 nights off) was repeated for at least 3 consecutive weeks prior to challenge with an individual probe. 2. Valproic acid was selected as a probe of both peroxisomal and microsomal beta-oxidase activity; antipyrine, phenytoin, quinidine, and carbamazepine were selected as probes of hepatic mixed-function oxidases (MFO), and lorazepam as a probe for UDP-glucuronosyl transferase activity. 3. Clearances of all probes except lorazepam, theophylline and phenytoin were approximately 20-30% faster in PB-treated than in control subjects; however, only in the case of carbamazepine did the increased clearance approach statistical significance. Neither phenytoin nor theophylline clearances were increased by PB. 4. A clearance index (probe CL for PB-treated subjects divided by probe CL for untreated subjects) was calculated for each probe, and an ordinal transformation of the log of the resultant ratio was plotted for each probe giving rise to a 'handprint' of the effect of PB on drug-metabolizing activity.     

The use of single sample clearance estimates to probe hepatic drug metabolism in rats. II

1. Single sample clearance estimates, Cl, were calculated for each of five drugs employed as probes of hepatic drug-metabolizing activity in rats. Probe drugs were theophylline, phenytoin, valproic acid, antipyrine, and S-warfarin. Cl values were calculated for each probe in animals pretreated with phenobarbital, isosafrole, beta-naphthoflavone, or clofibrate. Control animals were pretreated with vehicle only. 2. A clearance index (c.i., probe Cl after pretreatment divided by probe Cl control) was calculated for each probe and each pretreatment regimen, and data were consolidated to give different probe-based handprints of the pretreatment effects. 3. S-Warfarin was the least specific probe as its c.i. was greater than 1.0 subsequent to each pretreatment. Theophylline appeared to be the most selective probe since its c.i. deviated significantly from unity (3.56) only after beta-naphthoflavone pretreatment. Phenytoin exhibited c.i. values less than unity after each pretreatment indicating that it may not, when used as a single sample probe of hepatic drug-metabolizing activity, effectively discriminate between inductive or inhibitory effects of xenobiotics. 4. Multi-probe-based handprints of hepatic drug-metabolizing activity structured from simple single sample estimates of probe clearance have potential in the rapid screening of xenobiotic-induced alterations of drug-metabolizing enzyme activity.     

The use of single sample clearance estimates to probe hepatic drug metabolism in rats. I

1. Conditions were examined under which estimates of drug clearance made from a single measurement of plasma concentration effectively represented multisample estimates of clearance. When plasma concentrations were measured at various post-dose times, both individual and mean values of single sample clearance estimates, Cl, corresponded closely to multisample clearance estimates, Cl, and significant differences between Cl and Cl could not be detected. 2. Best post-dose sampling times were: theophylline, 6 h; phenytoin, 2 h; valproic acid, 20 min; antipyrine, 4 h; and S-warfarin, 48 h. 3. When theophylline clearance was evaluated by both multisample and single sample experiments during diethyl ether versus urethane anaesthesia, clearances were about 50% slower for ether-anaesthetized rats. This outcome was qualitatively and quantitatively the same regardless of whether single sample or multiple sample clearances were estimated, and single sample theophylline clearances were virtually identical to multisample clearances under both anaesthetic conditions. 4. We conclude that multiple drugs can be potentially useful for probing hepatic drug metabolizing activity in rats when using a single plasma measurement to estimate clearance. An appropriate array of such probes might effectively be used to handprint host-factor influences on drug metabolizing activity.     

An integral approach to drug craving

Drug craving is thought to be a critical factor in compulsive drug use and relapse after treatment; yet there has been little attempt to integrate the disparate research and theoretical writing on the topic from neurobiology, pharmacology, psychology, anthropology, philosophy, and religious/spiritual traditions into a cohesive theory of craving. As a result, the field lacks clear definitions from which to develop useful assessment tools and effective treatment interventions for craving. This article selectively reviews the current scientific literature on drug craving, and proposes a comprehensive theoretical framework that integrates western science with eastern and indigenous philosophical perspectives that have the potential to add rich texture to our understandings of craving.     

Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes.

Twenty-nine drugs of disparate structures and physicochemical properties were used in an examination of the capability of human liver microsomal lability data ("in vitro T(1/2)" approach) to be useful in the prediction of human clearance. Additionally, the potential importance of nonspecific binding to microsomes in the in vitro incubation milieu for the accurate prediction of human clearance was investigated. The compounds examined demonstrated a wide range of microsomal metabolic labilities with scaled intrinsic clearance values ranging from less than 0.5 ml/min/kg to 189 ml/min/kg. Microsomal binding was determined at microsomal protein concentrations used in the lability incubations. For the 29 compounds studied, unbound fractions in microsomes ranged from 0.11 to 1.0. Generally, basic compounds demonstrated the greatest extent of binding and neutral and acidic compounds the least extent of binding. In the projection of human clearance values, basic and neutral compounds were well predicted when all binding considerations (blood and microsome) were disregarded, however, including both binding considerations also yielded reasonable predictions. Including only blood binding yielded very poor projections of human clearance for these two types of compounds. However, for acidic compounds, disregarding all binding considerations yielded poor predictions of human clearance. It was generally most difficult to accurately predict clearance for this class of compounds; however the accuracy was best when all binding considerations were included. Overall, inclusion of both blood and microsome binding values gave the best agreement between in vivo clearance values and clearance values projected from in vitro intrinsic clearance data.     

An integrated model for prevention and treatment of drug abuse among American Indian youth.

American Indian youth have been shown to be at high risk for drug abuse. Epidemiological studies of Indian school students over the past two decades have revealed rates of use consistently higher than those found for other youth. Socioeconomic and historical factors have led to conditions that put a great deal of stress on the family and other support systems which in part account for the seriousness of the problem. A model is presented which can guide both prevention and treatment efforts addressing drug abuse in Indian communities. Five variable domains, social structure, socialization factors, psychological variables, peer associations and drug use, are related in an integrated structure. By following the progression of the etiological variables, a stepwise plan can be developed to organize interventions. Although the model has immediate utility, a number of further research questions are outlined that will enhance its application.     

The effect of roxatidine acetate and cimetidine on hepatic drug clearance assessed by simultaneous administration of three model substrates.

The effect of pretreatment for 7 days with either roxatidine acetate 75 mg twice daily or cimetidine 200 mg four times daily on the kinetics of antipyrine (AP), trimethadione (TMO) and indocyanine green (ICG) was studied in seven healthy, male, nonsmoking subjects. After pretreatment with cimetidine, the plasma clearances (CL) of AP and TMO were significantly lower and the elimination half-life (t1/2) of AP was significantly increased. The volumes of distribution (V) of AP and TMO were not affected. After roxatidine acetate, the pharmacokinetics of AP and TMO were unchanged. The cumulative renal excretion (% dose) and formation clearance of 3-hydroxymethyl-3-nor-antipyrine (NORA) were lowered by cimetidine treatment, but not following the administration of roxatidine acetate. ICG clearance was not changed significantly by either pretreatment. The results of this study show that roxatidine acetate does not impair the metabolism of three model substrates used to assess hepatic drug clearance.     

The use of single sample clearance estimates to probe hepatic drug metabolism: Handprinting the influence of phenobarbitone on human hepatic drug metabolism

1. Single sample clearance estimates, CL, were calculated for seven drugs employed as probes of human hepatic drug-metabolizing enzymes. Clearance estimates were calculated in healthy young adult male volunteers either taking no pretreatment, or taking phenobarbitone (PB) 100?mg nightly for 3 nights. This intermittent regimen (3 nights on, followed by 4 nights off) was repeated for at least 3 consecutive weeks prior to challenge with an individual probe.

2. Valproic acid was selected as a probe of both peroxisomal and microsomal β-oxidase activity; antipyrine, phenytoin, quinidine, and carbamazepine were selected as probes of hepatic mixed-function oxidases (MFO), and lorazepam as a probe for UDP-glucuronosyl transferase activity.

3. Clearances of all probes except lorazepam, theophylline and phenytoin were approximately 20-30% faster in PB-treated than in control subjects; however, only in the case of carbamazepine did the increased clearance approach statistical significance. Neither phenytoin nor theophylline clearances were increased by PB.

4. A clearance index (probe CL for PB-treated subjects divided by probe CL for untreated subjects) was calculated for each probe, and an ordinal transformation of the log of the resultant ratio was plotted for each probe giving rise to a ‘handprint' of the effect of PB on drug-metabolizing activity.     

The use of single sample clearance estimates to probe hepatic drug metabolism: handprinting the influence of cigarette smoking on human hepatic drug metabolism

1. Conditions were examined under which estimates of drug clearance made from a single measurement of plasma concentration effectively represented multiple-sample estimates of clearance for quinidine, valproic acid, unbound valproic acid, and lorazepam. When plasma concentrations were measured at various post-dose times, both individual and mean values of single-sample clearance estimates, CL, corresponded closely to multiple-sample clearance estimates. Best post-dose sampling times were: quinidine, 8 h; valproic acid, 24 h; and lorazepam, 24 h. 2. Single-sample clearance estimates, CL, were calculated for seven drugs employed as probes of human hepatic drug-metabolizing enzymes. Valproic acid was used to probe microsomal and peroxisomal beta-oxidase activity; antipyrine, phenytoin, quinidine, carbamazepine, and theophylline were used as probes of hepatic mixed-function oxidases (MFO), and lorazepam as a probe for UDP-glucuronosyltransferase activity. 3. A clearance index (CI, namely probe CL for smokers divided by probe CL for non-smokers) was calculated for each probe. The effect of cigarette smoking (and presumably polycyclic aromatic hydrocarbon exposure) on all probe CL values was consolidated and plotted as the logarithm of the CI to produce a handprint of drug metabolizing enzyme activity for cigarette smokers. 4. Only theophylline CL was significantly faster among smokers than non-smokers (P less than 0.01). 5. We conclude that the use of multiple probes of MFO activity when given in a single-dose, single-sample protocol for structuring handprints represents a minimally invasive and useful approach to characterize xenobiotic-mediated effects on hepatic MFO.