Showing papers on "Pharmacokinetics published in 1987"

Clinical Pharmacokinetics of 5-Fluorouracil and Its Metabolites in Plasma, Urine, and Bile

Abstract: Kinetics of 5-fluorouracil (FUra) and FUra metabolites in plasma and urine were investigated in 10 cancer patients following i.v. bolus administration of 500 mg/m2 FUra with 600 microCi of [6-3H]FUra. Biliary excretion was examined in two patients with external biliary catheters. Quantitation of unchanged drug and metabolites was assessed by a highly specific high-performance liquid chromatographic method. FUra plasma levels declined rapidly with an apparent elimination half-life of 12.9 +/- 7.3 min. Dihydrofluorouracil was detected within 5 min in most patients, demonstrating rapid catabolism and reached maximum peak levels of 23.7 +/- 9.9 microM at approximately 60 min. The apparent elimination half-life of dihydrofluorouracil (61.9 +/- 39.0 min) was consistently greater than that of the unchanged drug. The apparent elimination half-lives of the subsequent metabolites alpha-fluoro-beta-ureidopropionic acid and alpha-fluoro-beta-alanine were prolonged with values of 238.9 +/- 175.4 min and 1976 +/- 358 min, respectively. Approximately 60-90% of the administered dose was excreted in urine within 24 h, primarily as alpha-fluoro-beta-alanine. Biliary excretion accounted for 2-3% of total administered radioactivity. The major fraction of this radioactivity eluted on high-performance liquid chromatography as a previously unrecognized FUra metabolite. Analysis of its structure is currently ongoing in our laboratory. In conclusion, this study provides the first comprehensive analysis of the formation and excretion of FUra metabolites in plasma, urine, and bile following i.v. bolus administration of FUra in humans.

Disposition of propofol administered as constant rate intravenous infusions in humans.

Abstract: The disposition of the intravenous anesthetic propofol was studied when administered as a constant rate infusion at 3, 6, and 9 mg.kg-1.hr-1 for at least 2 hr to three groups of six patients each undergoing surgery under regional anesthesia. Arterial blood samples were collected at selected times during and up to 8 hr after infusion. Whole blood propofol concentrations were determined by high-performance liquid chromatography with fluorescence detection. Using a non-linear least-squares regression analysis, the individual data sets were best fitted by a three-compartment open mamillary model with central elimination in 17 patients. In one patient a biexponential equation was more appropriate. Derived pharmacokinetic parameters expressed as mean values +/- SD indicated an initial fast distribution (t1/2 pi; 2.8 +/- 1.2 min), with an intermediate phase (t1/2 alpha; 31.4 +/- 14.7 min), and a long terminal phase (t1/2 beta; 355 +/- 227 min), a large volume of distribution at steady state (Vss, 287 +/- 213 L), and a high blood clearance (Clb, 1.7 +/- 0.3 L/min). The function of drug in the central compartment in the terminal phase was low (Fc, 0.02). The elimination rate constant (K10, 0.1190 +/- 0.0351 min-1) was large compared with the other transfer rate constants and was responsible for the large amount of drug eliminated during distribution. The fraction of drug eliminated during the terminal phase amounted to 0.28. The slow return of drug from remote tissues (K31, 0.0033 +/- 0.0013 min-1) was rate limiting in the ultimate elimination.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase I clinical and pharmacokinetic study of taxol

Abstract: Taxol, selected for clinical trial because of its animal antitumor activity and unique structure and mechanism of action, was administered in Cremophor by i.v. infusion over 6 h in a phase I study. Eastern Cooperative Oncology Group toxicity grading was used. Eighty-three taxol courses were administered to 34 patients. Grade 3-4 hypersensitivity reactions occurred in 4 of 13 courses at the first 2 dose levels, but premedication with dexamethasone, diphenhydramine, and cimetidine resulted in only 3 additional Grade 2 reactions in the next 70 courses. Neurotoxicity, which resolved or improved after stopping therapy, was Grade 1 with 2 of 10 courses of 230 mg/m2 and Grades 1-3 after 11 of 12 courses of 275 mg/m2. Leukopenia, first seen (Grade 1) after 1 of 8 75 mg/m2 courses, was Grades 3-4 after 10 of 34 courses of 175-230 mg/m2 and 10 of 12 courses of 275 mg/m2. The WBC nadir occurred at a median of 10 days and the median time required for normalization of the WBC was 18 days. Alopecia began 2-3 weeks posttaxol in 2 of 9 patients treated with 75-135 mg/m2 and in all 16 patients (Grade 3) treated with 175-275 mg/m2. Grades 1-2 nausea and vomiting occurred in about one-third of the patients treated at a dose of 105 mg/m2 or more. Taxol disappearance from plasma was biphasic; half-lives of the first and second phases after a 275 mg/m2 dose were 0.32 and 8.6 h, respectively. The apparent volume of distribution was 55 liters/m2, and the peak plasma concentration with a dose of 275 mg/m2, which occurred immediately postinfusion, was approximately 8 microM. Only 5% of parent drug was excreted in the urine within 24 h. Minor objective responses were noted in one patient with gastric cancer and another with ovarian carcinoma. In addition, one patient with massive ascites due to metastatic adenocarcinoma from an unknown primary had only minimal sonographic evidence of ascites for 6 months posttreatment. Neurotoxicity and leukopenia were dose limiting in this schedule. The recommended phase II trial dose is 250 mg/m2, with premedication.

Plasma and cerebrospinal fluid pharmacokinetics of 3'-azido-3'-deoxythymidine: a novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases.

Abstract: We investigated the clinical pharmacokinetics of azidothymidine (N3TdR) as part of a phase I/II trial in the treatment of acquired immunodeficiency syndrome and related diseases. During the 6-week course of therapy, drug levels in plasma, cerebrospinal fluid, and urine were determined by HLPC. The plasma half-life of N3TdR was 1.1 hour. The total body clearance was 1.3 L/kg/hr. At intravenous doses of 5 mg/kg or oral doses of 10 mg/kg, plasma levels were continuously maintained above the target level of 1 mumol/L. Oral bioavailability was 63% +/- 13%. Substantial penetration of N3TdR into cerebrospinal fluid was demonstrated. At doses of 5 mg/kg intravenously or 10 mg/kg orally, cerebrospinal fluid drug levels exceeded and were maintained close to 1 mumol/L. Nineteen percent of the administered dose was excreted unchanged into the urine. Renal clearance was 0.23 L/kg/hr. N3TdR possesses pharmacokinetic properties that would facilitate the long-term treatment of patients with acquired immunodeficiency syndrome: it can be given orally and it penetrates the central nervous system.

Phase I trial of taxol given as a 24-hour infusion every 21 days: responses observed in metastatic melanoma.

Abstract: Taxol, a plant product, has significant activity against certain rodent and human xenograft tumors. It promotes microtubule assembly in vitro, in contrast to vinca alkaloids, which inhibit assembly. In this phase I study, taxol was administered as a 24-hour continuous intravenous (IV) infusion in 65 courses to 26 patients. A premedication regimen of dexamethasone, cimetidine, and diphenhydramine was used to prevent the acute hypersensitivity reactions observed in previous studies of taxol. Only one episode of mild stridor occurred in this study. Peripheral neuropathy was the dose-limiting toxicity and was observed in 40% of patients treated at a dose of 250 mg/m2. Significant neutropenia of brief duration was also common. Pharmacokinetic studies by a high-performance liquid chromatography (HPLC) method demonstrated that drug plasma concentrations increased during the 24-hour infusion and then declined rapidly. Peak plasma concentrations correlated with dose, and less than 5% of taxol was excreted in the urine. Most of the drug was bound to serum components. Partial responses of more than 3 months' duration were observed in four of 12 melanoma patients treated. The recommended phase II dose of taxol on this schedule is 250 mg/m2. Priority should be given to the study of taxol in melanoma.

Lamotrigine, a new anticonvulsant: Pharmacokinetics in normal humans

Abstract: The pharmacokinetics of lamotrigine, a new anticonvulsant, were studied in three studies in normal volunteers. In the first study, five subjects received oral doses of lamotrigine up to 240 mg. A linear relationship was observed between dose administration and both peak drug concentration and AUC. In a second study 10 subjects received 120 mg lamotrigine and the mean (+/- SD) of the elimination half-life (t1/2) was 24.1 +/- 5.7 hours and of volume of distribution/bioavailability 1.2 +/- 0.12 L/kg. Saliva concentrations were 46% of the plasma concentration. Total urinary recovery of drug over 144 hours was 70.5% of the oral dose. A glucuronide conjugate accounted for 89.4% of the urinary recovery. In a third study the kinetics of repeated administration were studied. Fifteen subjects were randomized to lamotrigine (n = 10) or placebo (n = 5) and received multiple doses over 7 days. The overall plasma elimination t1/2 calculated from data during the 7 days was 25.5 +/- 10.2 hours. Observed pharmacokinetics on multiple administration obeyed closely those predicted from the single-dose experiment, suggesting the absence of autoinduction of metabolism. No clinically important side effects or changes in central nervous system or cardiovascular system variables, hematology, biochemistry, or urinalysis occurred during the 7 days.

Clinical pharmacokinetics of ethanol

Abstract: The pharmacokinetics of ethanol after typical doses are described by a 1-compartment model with concentration-dependent elimination. The volume of distribution estimated from blood concentrations is about 37 L/70 kg. Protein binding of ethanol has not been reported. Elimination is principally by metabolism in the liver with small amounts excreted in the breath (0.7%), urine (0.3%), and sweat (0.1%). Metabolism occurs, principally by alcohol dehydrogenase, in the liver to acetaldehyde. Models of ethanol input and absorption are crucial to the description and understanding of the effects of ethanol dose on bioavailability. Little attention has been paid to evaluation of potential models. First-pass extraction of ethanol is predicted to be dependent on hepatic blood flow and ethanol absorption rate, with a typical extraction ratio of 0.2. The overall elimination process can be described by a capacity-limited model similar to the Michaelis-Menten model for enzyme kinetics. The maximum rate of elimination of ethanol (elimination capacity or Vmax is 8.5 g/h/70 kg. This would be equivalent to a blood ethanol disappearance rate of 230 mg/L/h if metabolism took place at its maximum rate. The elimination rate is half of the elimination capacity at a peripheral blood ethanol concentration (Km) of about 80 mg/L. Ethanol is readily detectable in expired air. The usual blood:expired air ratio is 2300:1 and breath clearance at rest is 0.16 L/h. The renal clearance of ethanol is 0.06 L/h and sweat clearance is 0.02 L/h. The use of a zero-order model of ethanol elimination has been widespread although the limitations of this model have been known for a long time. Much of the published work on ethanol pharmacokinetics must be regarded with suspicion because of this assumption.

Pharmacokinetic interactions of cimetidine 1987.

Abstract: The number of studies on drug interactions with cimetidine has increased at a rapid rate over the past 5 years, with many of the interactions being solely pharmacokinetic in origin. Very few studies have investigated the clinical relevance of such pharmacokinetic interactions by measuring pharmacodynamic responses or clinical endpoints. Apart from pharmacokinetic studies, invariably conducted in young, healthy subjects, there have been a large number of in vitro and in vivo animal studies, case reports, clinical observations and general reviews on the subject, which is tending to develop an industry of its own accord. Nevertheless, where specific mechanisms have been considered, these have undoubtedly increased our knowledge on the way in which humans eliminate xenobiotics. There is now sufficient information to predict the likelihood of a pharmacokinetic drug-drug interaction with cimetidine and to make specific clinical recommendations. Pharmacokinetic drug interactions with cimetidine occur at the sites of gastrointestinal absorption and elimination including metabolism and excretion. Cimetidine has been found to reduce the plasma concentrations of ketoconazole, indomethacin and chlorpromazine by reducing their absorption. In the case of ketoconazole the interaction was clinically important. Cimetidine does not inhibit conjugation mechanisms including glucuronidation, sulphation and acetylation, or deacetylation or ethanol dehydrogenation. It binds to the haem portion of cytochrome P-450 and is thus an inhibitor of phase I drug metabolism (i.e. hydroxylation, dealkylation). Although generally recognised as a nonspecific inhibitor of this type of metabolism, cimetidine does demonstrate some degree of specificity. To date, theophylline 8-oxidation, tolbutamide hydroxylation, ibuprofen hydroxylation, misonidazole demethylation, carbamazepine epoxidation, mexiletine oxidation and steroid hydroxylation have not been shown to be inhibited by cimetidine in humans but the metabolism of at least 30 other drugs is affected. Recent evidence indicates negligible effects of cimetidine on liver blood flow. Cimetidine reduces the renal clearance of drugs which are organic cations, by competing for active tubular secretion in the proximal tubule of the kidney, reducing the renal clearances of procainamide, ranitidine, triamterene, metformin, flecainide and the active metabolite N-acetylprocainamide. This previously unrecognised form of drug interaction with cimetidine may be clinically important for both parent drug, and metabolites which may be active.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics of propofol in female patients. Studies using single bolus injections.

Abstract: The pharmacokinetics of propofol in a dose of 2.5 mg kg−1 given via a vein in the antecubital fossa were studied in 18 patients. Anaesthesia was maintained with nitrous oxide in oxygen in all patients. The effects of pretreatment with fentanyl (n = 6) and maintenance with halothane (n = 6) on the pharmacokinetics of propofol were also investigated. Pretreatment with fentanyl resulted in prolonged apnoea in four patients. No serious side effects occurred. The pharmacokinetics of propofol in unpretreated patients who were maintained with nitrous oxide in oxygen only can be described by a three-compartment open mammalian model with very rapid distribution (T½β about 3 min), rapid elimination (T½β 45 min) and a slower final phase (T½γ about 300 min). The total body clearance of propofol was rapid (1.91 litre min−1). Propofol was initially distributed into a relatively large central compartment (41.3 litre) and was extensively redistributed (V55 305 litre; Vγ 722 litre). Throughout the sampling period the mean blood concentrations of propofol for the patients pretreated with fentanyl were about 50% higher than the mean concentrations for patients maintained with nitrous oxide only. Mean propofol concentrations for the patients maintained with halothane were intermediate between those of the other two groups.

Clinical pharmacokinetics of anti-parkinsonian drugs.

Abstract: Of the neurological disorders, none can claim a battery of therapeutic agents based upon as rational a pharmacology as can Parkinson's disease. In this review, the clinical pharmacokinetics of the major classes of anti-Parkinsonian drugs is discussed. Although they are the oldest drugs in the anti-Parkinsonian armamentarium, little pharmacokinetic data are available regarding the anticholinergic and antihistaminic agents. Based on elimination half-lives of 10 to 18 hours, most could probably be effectively given on a twice-daily schedule. Amantadine is unique among anti-Parkinsonian agents both in lacking a clearly defined mechanism of action and in being eliminated from the body exclusively by renal excretion of unchanged drug. Thus the normal decline of renal function in the elderly Parkinsonian population becomes an important factor in avoiding potential drug toxicity. The pharmacokinetics and pharmacodynamics of levodopa are complex. Since it is an amino acid, it follows metabolic pathways and must compete for absorption and brain uptake with a number of large neutral amino acids. It has a short elimination half-life and, as Parkinson's disease progresses, the brain loses its capacity to store the drug and becomes dependent in a moment-to-moment fashion on plasma levodopa concentrations, creating therapeutic response fluctuations in over 50% of patients. Pharmacokinetic considerations in the management of these response fluctuations are discussed. The newest class of anti-Parkinsonian agents are the direct acting dopamine receptor agonists. These drugs, all derivatives of ergot, have more prolonged durations of anti-Parkinsonian action than levodopa. However, other than bromocriptine, clinical experience with members of this class of drugs is still limited.

Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man

Abstract: The pharmacodynamics of a racemic mixture of ketamine R,S (±)-ketamine and of each enantiomer, S(+)-ketamine and R(−)-ketamine, were studied in five volunteers. The median frequency of the electroencephalogram (EEG) power spectrum, a continuous noninvasive measure of the degree of central nervous system (CNS) depression (pharmacodynamics), was related to measured serum concentrations of drug (pharmacokinetics). The concentration-effect relationship was described by an inhibitory sigmoid Emax pharmacodynamic model, yielding estimates of both maximal effect (Emax) and sensitivity (IC50) to the racemic and enantiomeric forms of ketamine. R(−)-ketamine was not as effective as R,S(±)-ketamine or S(+)-ketamine in causing EEG slowing. The maximal decrease (mean±SD) of the median frequency (Emax)for R(−)-ketamine was 4.4±0.5 Hz and was significantly different fromR,S (±)-ketamine (7.6 ±1.7 Hz) and S(+)-ketamine (8.3±1.9Hz). The ketamine serum concentration that caused one-half of the maximal median frequency decrease (IC50) was 1.8±0.5Μg/mL for R(−)-ketamine; 2.0±0.5 Μg/mL for R,S(±)-ketamine; and 0.8±0.4 Μg/mL for S(+)-ketamine. Because the maximal effect (Emax) of the R(−)-ketamine was different from that of S(+)-ketamine and R,S(±)-ketamine, it was not possible to directly compare the potency (i.e., IC50) of these compounds. Accordingly, a classical agonist/partial-agonist interaction model was examined, using the separate enantiomer results to predict racemate results. Although the model did not predict racemate results well, its failure was not so great as to provide clear evidence of synergism (or excess antagonism) of the enantiomers.

Ketorolac tromethamine absorption, distribution, metabolism, excretion, and pharmacokinetics in animals and humans.

Abstract: Ketorolac tromethamine (KT), a potent non-narcotic analgesic, with cyclooxygenase inhibitory activity, was administered (14C-labeled and unlabeled) intravenously (iv), orally (po), and intramuscularly (im) in solution to humans, cynomolgus monkeys, rabbits, rats, and mice. KT was absorbed rapidly (Tmax less than 1.0 hr) and efficiently (greater than 87%) following po and im doses in all species. The plasma half-life of ketorolac (K) ranged from 1.1 hr (rabbits) to 6.0 hr (humans). The protein binding of K ranged from 72.0% (mouse) to 99.2% (humans). Linear pharmacokinetics of K was observed in the mouse after single oral doses of KT ranging from 0.25 to 16 mg/kg. Radioactivity was excreted predominantly into urine, ranging from 78.9% (mouse) to 102% (monkey) following iv doses. The dose was excreted into urine primarily as K conjugates, K, and p-hydroxy-K in humans. The monkey was similar to humans with respect to kinetics, but did not form the p-hydroxy metabolite. The rabbit was unusual in that it exhibited substantial presystemic metabolism (50%). The rat excreted a much higher percentage of radioactivity into the feces and formed an additional unidentified metabolite. The most comparable species with respect to humans metabolically was the mouse. The metabolism and excretion of K was similar following iv, po, and im doses within each species studied.

Antibiotic pharmacokinetics in cystic fibrosis. Differences and clinical significance.

Abstract: Antibiotics are administered to cystic fibrosis patients for chronic endobronchial infection complicated by frequent exacerbations. Agents active against Staphylococcus aureus, Pseudomonas aeruginosa or both are administered. Serum antibiotic concentrations were measured in cystic fibrosis patients in an effort to optimise antibiotic dose and frequency. This led to the observation that cystic fibrosis subjects had (in general) a larger Vd and increased total body clearance of beta-lactams and aminoglycosides than non-cystic fibrosis subjects. The larger Vd is mainly due to the increased amount of lean body mass per kg bodyweight, although increased tissue binding may also account for part of this. The increased total body clearance of beta-lactams appears to be due to increased renal elimination, particularly tubular secretion. Decreased tubular reabsorption and increased non-renal clearance contribute to the increased total body clearance of metabolised beta-lactams and aminoglycosides. However, the lack of concomitant controls in many studies make these generalisations tentative. The result of the apparent cystic fibrosis-specific differences is lower peak serum antibiotic concentrations, a smaller AUC, and a shorter elimination half-life than non-cystic fibrosis subjects. Since sputum (and bronchial mucosal) concentration is dependent on the peak serum concentration (and AUC), cystic fibrosis subjects require larger doses of most antibiotics more frequently. Newer quinolones may be an exception. Studies comparing the efficacy and safety of larger and more frequent antibiotic doses to conventional therapy are not available. Although it appears logical to mimic serum antibiotic concentrations found in non-cystic fibrosis subjects, the lack of information on the ideal sputum concentration versus time curve should temper our enthusiasm for cystic fibrosis-specific dosage regimens.

Pharmacokinetics of ofloxacin after parenteral and oral administration.

Abstract: In 10 volunteers, the pharmacokinetics of ofloxacin [HOE 280, DL 8280; (+/-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H -pyrido-[1,2,3-de] [1,4]benzoxacine-6-carboxylic acid] was determined after administration of 25, 50, 100, and 200 mg intravenously (30-min infusion) as well as 200 and 400 mg orally. Concentrations in serum and urine were measured by high-pressure liquid chromatography. Concentrations in serum following different parenteral ofloxacin dosages demonstrated dose dependency with long biological half-lives of 231 to 267 min. Pharmacokinetic parameters were calculated on the basis of open two- and three-compartment models, which yielded nearly identical results. High volumes of distribution (1.2 to 1.4 liters/kg of body weight) suggested effective diffusion into the extravascular space. High total and renal clearances indicated primarily renal excretion with additional elimination pathways, such as tubular secretion and extrarenal elimination. After oral administration, absorption was excellent, and the absolute bioavailability following 200 mg of ofloxacin could be calculated at greater than 0.95. Maximal concentrations in serum were attained 1.2 to 1.9 h after dosing; areas under the curve increased in proportion to dose between 200 and 400 mg of oral ofloxacin. The amount of known metabolites (demethyl and N-oxide compounds) excreted in urine reached only 4.3% (intravenously) and 4.0% (orally). Transient headaches in some volunteers were the only side effects registered.

Pharmacokinetics and disposition of carvedilol in humans.

Abstract: Pharmacokinetics of carvedilol (C) have been studied in healthy volunteers after a single i.v. and oral administration, and the metabolic disposition after oral administration of 14C-labeled drug. C demonstrates dose-linear behavior. The absolute bioavailability reaches 24% probably due to a first-pass effect. After a 50 mg oral dose, maximum concentrations of 66 micrograms/l are achieved within 1.2 h. C is extensively distributed to the tissues (Vz = 132 l) and eliminated primarily by hepatic metabolism (total clearance 590 ml/min, renal clearance 4 ml/min). Because of the longer half-life of 6.4 h after oral administration in contrast to 2.4 h after i.v. administration, C is assumed to be absorption dependent since no sustained-release formulation was used. The half-life of radioactivity in plasma is 39 h; 16% of C is excreted in urine in the form of metabolites and only 0.3% unchanged. The urinary metabolites consist of carvedilol glucuronide (5.2% of the dose), cleavage products of the beta-blocking side chain (2.1%), and ring-hydroxylated forms (2.9%). Sixty percent of the dose is recovered in the feces. A demethylated product of C exhibits only minor beta-blocking activity. This metabolite is detected in plasma in concentrations ten times lower than the parent compound.

High-performance liquid chromatographic assay for taxol in human plasma and urine and pharmacokinetics in a phase I trial

Abstract: Taxol is a unique antineoplastic agent which appears to exert its cytotoxic action as a result of interference with microtubular structure and function. Clinical development of this drug will be facilitated by the availability of sensitive and specific methods for its quantitation in biological fluids. We have developed a reverse-phase high-performance liquid chromatographic assay for taxol capable of detecting concentrations as low as 50 nM, which can be automated using readily available equipment. With this assay we have performed pharmacologic studies of taxol during the conduct of a phase I trial of this compound at The Johns Hopkins Oncology Center. Following a 60- to 360-minute infusion, the plasma disappearance is biexponential, with harmonic mean alpha half-life and beta half-life values of 16.2 minutes and 6.4 hours, respectively. Volumes of distribution for the theoretical central compartment (VDc) and at steady state (VDss) were 8.6 and 67.1 L/m2. Mean plasma clearance was 253 ml/minute/m2. Urinary clearance was 29.3 ml/minute/m2 and 5.9% +/- 8.8% of the drug was identified in 48-hour urine collections. No metabolites have been identified. Over the 18-fold dose range studied, there was no evidence of nonlinearity or dose-dependent behavior. A rough correlation between area under the plasma disappearance curve and hematologic toxicity was observed.

Plasma protein binding of drugs in the elderly

Abstract: Binding to plasma proteins can affect the pharmacokinetics and pharmacodynamics of drugs. Age is one of many factors which can affect plasma protein binding of drugs. Unfortunately, very few generalities can be drawn from the studies of the effect of age on protein binding. Whether age has an effect on protein binding is dependent not only on the drug, but also on the manner in which the study is conducted. Several studies involve patients with various disease states making assessment of the effect of age alone on protein binding difficult. Results of different studies on the same drug do not always agree--in one case finding no change in protein binding with age and in another, a significant increase or decrease in protein binding. Most drugs which exhibit increased binding (decreased free fraction) in elderly subjects are basic and tend to have a greater affinity for alpha 1-acid glycoprotein than for albumin. The list of drugs exhibiting decreased binding (increased free fraction) in the elderly is longer and includes both acidic and basic drugs. The impact of changes in protein binding with age is dependent on the magnitude of the change, on the pharmacokinetic characteristics of the drug and on its therapeutic index. Some changes, although statistically significant, are not likely to be of importance clinically. From the studies reviewed, the free fraction is changed by greater than 50% in the elderly for only a few drugs, e.g. acetazolamide, diflunisal, etomidate, naproxen, salicylate, valproate and zimeldine.

Comparison of steady-state pharmacokinetics of two dosage regimens of vancomycin in normal volunteers.

Abstract: A pharmacokinetic comparison of the two recommended dosages of vancomycin given as multiple doses has not been previously performed. Eleven adult subjects with normal renal function randomly received 500 mg every 6 h (five doses) and, later, 1,000 mg every 12 h (three doses). Each dose was infused over 1 h, and regimens were separated by 1 week. Compared with the two-compartment fit, a three-compartment fit significantly reduced the residual weighted sums of squares. Accumulation occurred for both regimens after repeated dosing and was independent of dose. At steady state, concentrations in serum at 1 h showed little variation for the 1,000- or the 500-mg dose regimen (33.7 +/- 3.8 versus 22.6 +/- 3.2 micrograms/ml); trough concentrations were 7.9 +/- 1.7 versus 11.2 +/- 2.2 micrograms/ml, respectively. With the 1,000-mg dose, the terminal half-life was 7.7 +/- 1.8 h, steady-state area under the curve for the dose interval was 227 +/- 28.3 micrograms X h/ml, and total body clearance was 86.1 +/- 8.9 ml/min per 1.73 m2. The red-man syndrome occurred in 9 of 11 volunteers who received 1,000-mg doses and in none of those who received 500-mg doses. We concluded that vancomycin disposition in healthy adults with normal renal function is best described by a three-compartment model, there is relatively little variation in vancomycin disposition in normal volunteers, significant accumulation occurs with multiple dosing, it is inappropriate to use the same therapeutic window for both regimens, and the pharmacokinetics of vancomycin justify a 12-h dose interval; however, a 1-g dose is associated with a significantly greater incidence of the red-man syndrome.

Alcohol consumption in free-feeding rats: procedural, genetic and pharmacokinetic factors.

Abstract: Voluntary consumption of alcohol by rats (i.e. in the absence of food or water deprivation, sweetening of the alcohol solution, etc.) that results in the attainment of behaviorally significant or pharmacologically detectable blood alcohol levels (BALs) has been difficult to demonstrate. In this study, we showed that free-feeding Wistar rats given access to increasingly concentrated solutions of alcohol in separate “drinking” cages on a 1-h per day basis drank on average close to 1 g/kg, resulting in average BALs close to 50 mg%. This drinking was comparable to that obtained by rats trained according to a procedure used widely by others in which animals are maintained at reduced body weights. Weight restriction alone, however, did not enhance amount of alcohol consumption over that of free-feeding animals in the 1-h session. There was also a strain difference in that Wistar rats drank significantly more than did Sprague-Dawley rats. Post hoc absorption curves showed that the initial absorption of alcohol from both the stomach and the peritoneum was slower in Wistar than in Sprague-Dawley rats, suggesting rate of absorption may be inversely related to amount of alcohol consumed; metabolic rates and volumes of distribution appeared unrelated to consumption. This periodic availability paradigm might be useful to investigate the effect of biological variables on individual bouts of alcohol consumption.

Pharmacokinetics and tissue distribution of oxytetracycline in carp (Cyprinus carpio L.) following different routes of administration.

Abstract: . The objective of this pharmacokinetic study was to investigate absorption, distribution, elimination and bioavailability of oxytetracycline (OTC) in carp, Cyprinus carpio L., after different routes of administration, OTC was administered intravenously (i.v.), intramuscularly (i.m.) and orally at 60 mg/kg body weight. OTC levels were determined in plasma and several tissues. Analysis of the plasma drug concentration-time curves following i.v. OTC injection revealed three distinct phases. A three-compartment open model was used to derive pharmacokinetic parameters. Compared to mammals, a very extended final elimination half-life was observed (139.8±38.1 h). Following i.m. OTC administration, Cmax was 56.8±10.9μg OTC/ml at 14 h post-injection. The Vd area was 2.1 ± 0.66 1/kg. Extreme differences were observed with respect to bioavailability following i.m. and oral administration; approximately 80 and 0.6%, respectively. Following i.m. injection tissue OTC determinations revealed that the drug was accumulating in pronephros, bone tissue and scales. After 21 days the OTC concentrations were 2.9±0.8, 5.2±0.3 and 4.7±3.1 μg/ ml, respectively. In tissue samples from the dorsal region (muscle), including the injection site, OTC could not be demonstrated at that time. The pharmacokinetic data are discussed in relation to the susceptibility of the immune system of fish for modulation.

Pharmacokinetics and Dose Proportionality of Loratadine

Abstract: The dose proportionality and pharmacokinetics of loratadine, a new nonsedating antihistamine, were studied in 12 normal volunteers. In a three-way cross-over, each volunteer received a single 10-, 20-, or 40-mg loratadine capsule. Blood was collected up to 96 hours after dosing. Plasma loratadine concentrations were determined by radioimmunoassay (RIA), and those of a minor, but active metabolite, descarboethoxyloratadine, by high performance liquid chromatography (HPLC). Concentrations in the disposition phase were fitted to a biexponential equation for pharmacokinetic analysis. For dose proportionality, AUC- and Cmax-dose relationships were evaluated by linear regression. Also, pharmacokinetic parameters and dose-adjusted AUCs were compared by analysis of variance. Loratadine was rapidly absorbed, reaching Cmax values (4.7, 10.8, and 26.1 ng/mL) at 1.5, 1.0 and 1.2 hours for the 10-, 20-, and 40-mg doses, respectively. The loratadine t1/2 beta ranged from 7.8 to 11.0 hours. Descarboethoxyloratadine reached Cmax values (4.0, 9.9, and 16.0 ng/mL) at 3.7, 1.5, and 2.0 hours for the 10-, 20-, and 40-mg doses, respectively. Its t1/2 beta ranged from 17 to 24 hours. For both compounds, AUC- and Cmax-dose relationships were linear and there were no differences in the t1/2 beta, CL/F, or dose-adjusted AUC values among the treatments. Loratadine and descarboethoxyloratadine plasma concentrations and pharmacokinetics were not dose dependent.

Peripheral pharmacokinetics of levodopa in untreated, stable, and fluctuating parkinsonian patients.

Abstract: We compared the pharmacokinetics of oral and IV infusions of levodopa in untreated, stable, and fluctuating patients pretreated with carbidopa. After oral dosing, mean peak plasma levodopa levels, time to peak level concentration after oral levodopa, and area under the curve were similar in all groups. Absorption was proportional to dose. Plasma elimination half-lives, clearance rates, and volumes of distribution after levodopa infusions were similar in all groups. 3-O-Methyldopa levels were similar in stable and fluctuating subjects. We conclude that the peripheral pharmacokinetics of levodopa do not differ between untreated, stable, and fluctuating patients, and that altered peripheral kinetics of the drug are unlikely to explain the development of the fluctuating state.

A comparative study on the pharmacokinetics of methotrexate in a dose range of 0.5 g to 33.6 g/m2 in children with acute lymphoblastic leukemia

Abstract: Concentrations of methotrexate have been determined in the serum and cerebrospinal fluid after 406 infusions of methotrexate to 58 children with acute lymphoblastic leukemia. The dose of methotrexate varied between 500 mg/m2 and 33 600 mg/m2. Pharmacokinetic analysis of the data has been carried out. The effect of dose, age, and number of treatments on steady-state concentration, serum half-life, cerebrospinal fluid (CSF) serum distribution ratio, volume of distribution, systemic clearance of methotrexate was examined. The elevation of dose resulted in a nonproportional increase of the steady-state concentrations both in serum and CSF. The great inpatient and interpatient variations of steady-state concentrations caused only statistically not significant differences in the parameters of different subgroups of dosages. Correlation was found between concentrations of methotrexate in serum and CSF. One to 4 years old children were found to have lower steady-state concentrations of methotrexate in the serum and CSF, greater volume of distribution and faster clearence of the drug. Dose-dependency and age-dependency of methotrexate pharmacokinetics has been concluded.

Determinants of benzodiazepine brain uptake: lipophilicity versus binding affinity.

Abstract: Factors influencing brain uptake of benzodiazepine derivatives were evaluated in adult Sprague Dawley rats (n = 8-10 per drug). Animals received single intraperitoneal doses of alprazolam, triazolam, lorazepam, flunitrazepam, diazepam, midazolam, desmethyldiazepam, or clobazam. Concentrations of each drug (and metabolites) in whole brain and serum 1 h after dosage were determined by gas chromatography. Serum free fraction was measured by equilibrium dialysis. In vitro binding affinity (apparent Ki) of each compound was estimated based on displacement of tritiated flunitrazepam in washed membrane preparations from rat cerebral cortex. Lipid solubility of each benzodiazepine was estimated using the reverse-phase liquid chromatographic (HPLC) retention index at physiologic pH. There was no significant relation between brain:total serum concentration ratio and either HPLC retention (r = 0.18) or binding Ki (r = -0.34). Correction of uptake ratios for free as opposed to total serum concentration yielded a highly significant correlation with HPLC retention (r = 0.78, P less than 0.005). However, even the corrected ratio was not correlated with binding Ki (r = -0.22). Thus a benzodiazepine's capacity to diffuse from systemic blood into brain tissue is much more closely associated with the physicochemical property of lipid solubility than with specific affinity. Unbound rather than total serum or plasma concentration most accurately reflects the quantity of drug available for diffusion.

Clinical pharmacokinetics of nicotine.

Abstract: Nicotine intake is considered to be a major factor in sustaining tobacco addiction. For this reason, nicotine gum has recently been introduced as an adjuvant to smoking cessation. The introduction of nicotine as a 'therapeutic' entity necessitates a careful examination of its clinical pharmacokinetics. Insufficient data exist to quantitatively assess the absorption of nicotine after oral administration. Based upon physicochemical and pharmacokinetic principles, the oral bioavailability of nicotine would be expected to be less than 20%. The limited data available in the literature appear to support this conclusion. Absorption from the oral mucosa is the principal site of nicotine absorption in subjects who chew tobacco or nicotine gum. Absorption by this route is highly pH dependent. Nicotine is also readily absorbed from the nasal mucosa, and after topical administration. Nicotine distributes extensively into body tissues with a volume of distribution ranging from 1.0 to 3.0 L/kg. Nicotine has been shown to transfer across the placenta and into breast milk in humans. Plasma protein binding is negligible, ranging from 4.9 to 20%. The predominant route of nicotine elimination is hepatic metabolism. Although a number of metabolites of nicotine have been identified, it is unclear whether any of these compounds contribute to the pharmacological effect of nicotine. Nicotine is also excreted unchanged in urine in a pH-dependent fashion. With urinary pH less than 5, an average 23% of the nicotine dose is excreted unchanged. When urinary pH is maintained above 7.0, unchanged nicotine urinary excretion drops to 2%. After intravenous administration, nicotine exhibits biexponential decline in plasma. Total plasma clearance ranges from 0.92 to 2.43 L/min. During urinary acidification, renal clearance averages 0.20 L/min. Non-renal blood clearance averages 1.2 L/min, indicating that nicotine elimination is dependent on hepatic blood flow. The literature is devoid of information regarding the effect of disease on the pharmacokinetics of nicotine. Based upon the drug's pharmacokinetics in healthy smokers, it would be anticipated that disease states which alter hepatic blood flow may have the greatest impact on nicotine pharmacokinetics. In addition, drugs which alter hepatic blood flow may cause significant alterations in the systemic clearance of nicotine. Dependence on smoking appears to be related, at least in part, to the achievement of a rapid rise in plasma nicotine concentrations. If this assessment is correct, the most desirable adjuvant for smoking cessation would be one that closely mimics this pattern of plasma nicotine concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical pharmacodynamics of continuous infusion teniposide: Systemic exposure as a determinant of response in a Phase I trial

Abstract: Teniposide (VM-26) is an effective anticancer drug usually administered as a short infusion in doses of 150 to 165 mg/m2. The objectives of the trial reported here were to evaluate clinical responses and assess pharmacokinetic parameters as a determinant of outcome when VM-26 was administered as a 72-hour continuous infusion (CI) with doses escalated from 300 to 750 mg/m2 per course. Twenty-eight patients with recurrent leukemia, lymphoma, or neuroblastoma received 53 courses of CI VM-26 and 16 had measurable responses. There were two partial remissions and one stable disease among seven neuroblastoma patients and 13 of 21 leukemia/lymphoma patients had oncolytic responses (greater than or equal to 75% decrease in circulating blasts). Toxicity included moderate to severe mucositis and myelosuppression. Pharmacokinetic parameters determined during 35 courses administered to 23 patients were highly variable. Clearance (CI) ranged between 3.7 and 43.8 ml/min/m2, resulting in VM-26 plasma concentrations from ...

The mechanism of the warfarin-rifampin drug interaction in humans

Abstract: The mechanism of the drug interaction in humans between warfarin and rifampin was investigated by monitoring the elimination kinetics and metabolic disposition of a single oral dose of pseudoracemic warfarin by GC/MS. The decrease in hypoprothrombinemia observed with concomitant administration of therapeutic doses of rifampin was accompanied by a substantial decrease in the elimination half-lives of both warfarin enantiomers. Rifampin increased the clearance of (R)-warfarin threefold and the clearance of (S)-warfarin twofold. The excretion profiles for warfarin and its metabolites in urine and feces were similar for both control and treated subjects with the exception that 4'-hydroxywarfarin (stereoselective for the (S)-enantiomer) was observed when rifampin was administered. 4'-Hydroxywarfarin is a metabolite of the drug hitherto undetected in vivo in humans. Based on formation clearance values estimated for 6-, 7-, and 8-hydroxywarfarin, rifampin appears to increase the clearance of the parent drug by induction of the cytochrome P-450 isozyme(s) responsible for aromatic hydroxylation.