Showing papers on "Pharmacokinetics published in 1988"

Fluorouracil: biochemistry and pharmacology.

Abstract: Fluorouracil (5FU) is still considered the most active antineoplastic agent in the treatment of advanced colorectal cancer. The drug needs to be converted to the nucleotide level in order to exert its effect. It can be incorporated into RNA leading to interference with the maturation of nuclear RNA. However, its conversion to 5-fluoro-2'deoxy-5' monophosphate (FdUMP) leading to inhibition of thymidylate synthase (TS) and subsequently of DNA synthesis, is considered to be its main mechanism of action. In the presence of a folate cofactor a covalent ternary complex is formed, the stability of which is the main determinant of the action of 5FU. Resistance against 5FU can be mainly attributed to aberrations in its metabolism or to alterations of TS, eg, gene amplification, altered kinetics in respect to nucleotides or folates. Biochemical modulation of 5FU metabolism can be applied to overcome resistance against 5FU. A variety of normal purines, pyrimidines, and other antimetabolites have been studied in this respect, but only some of them have been clinically successful. Delayed administration of uridine has recently been shown to "rescue" mice and patients from toxicity, while pretreatment with leucovorin is the most promising combination to enhance the therapeutic efficacy. 5FU is frequently administered in an intravenous (IV) injection, and shows a rapid distribution and a triphasic elimination. The nonlinearity of 5FU pharmacokinetics is related to saturation of its degradation. Continuous infusion of 5FU led to different kinetics. Regional administration, such as hepatic artery infusion, offers a way to achieve higher drug concentrations in liver metastases and is accompanied by lower systemic concentration. The current status of the biochemical and pharmacokinetic data is reviewed.

Recombinant Human Tumor Necrosis Factor Administered as a 24-Hour Intravenous Infusion. A Phase I and Pharmacologic Study

Abstract: Recombinant human tumor necrosis factor (rH-TNF) is a cytokine with direct antitumor properties. In a phase I trial we continuously infused rH-TNF for 24 hours. We gave a total of 115 courses of therapy to 50 patients. Doses ranged from 4.5 to 645 micrograms of rH-TNF/m2. Systemic toxicity, including fever, chills, fatigue, and hypotension, increased with the dose of rH-TNF administered. Doses greater than 454 micrograms/m2 frequently caused severe lethargy and fatigue, which precluded hospital discharge of the patient at the completion of therapy. The dose-limiting toxicity was hypotension, and five patients treated at the two highest dose levels required dopamine treatment. Other organ-specific toxicity was modest and spontaneously resolved after 48 hours. The 24-hour infusions of rH-TNF were associated with significant decreases in serum cholesterol and high-density lipoprotein levels. Pharmacokinetic studies using an enzyme-linked immunosorbent assay demonstrated peak plasma rH-TNF levels of 90-900 pg/mL. Despite continuous infusion of rH-TNF, no steady-state level was achieved. The recommended phase II dose for rH-TNF as a 24-hour continuous infusion is 545 micrograms/m2.

Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine.

Abstract: The pharmacokinetics and bioavailability of N-acetylcysteine (NAC) have been determined after its intravenous and oral administration to 6 healthy volunteers. According to a randomized cross-over design each subject received NAC 200 mg i.v. and 400 mg p.o., and blood samples were collected for 30 h. Reduced NAC had a volume of distribution (VSS) of 0.59 l.kg-1 and a plasma clearance of 0.84 l.h-1.kg-1. The terminal half-life after intravenous administration was 1.95 h. The oral bioavailability was 4.0%. Based on total NAC concentration, its volume of distribution (VSS) was 0.47 l.kg-1 and its plasma clearance was 0.11 l.h-1.kg-1. The terminal half-life was 5.58 h after intravenous administration and 6.25 h after oral administration. Oral bioavailability of total NAC was 9.1%.

Pharmacokinetics and protein binding of propofol in patients with cirrhosis.

Abstract: The pharmacokinetics and protein binding of propofol were studied in ten patients with cirrhosis and in ten control patients undergoing elective surgery. All patients received 2.5 mg.kg-1 propofol as an intravenous bolus injection for the induction of anesthesia. Whole blood propofol concentrations were measured at intervals up to 12 h, using a high-performance liquid chromatography (HPLC) technique. Propofol protein binding was estimated by equilibrium dialysis 10 min after injection of propofol. Individual propofol profiles for all patients were best described by a three-compartment open mammillary model. Rapid and slow propofol distribution half-times were observed, followed by an elimination phase with a half-time of 4-5 h. Propofol total body clearance was reduced (1.99 +/- 0.68 l.min-1) in the patients with cirrhosis but did not differ significantly from that in the control patients (2.30 +/- 0.61 l.min-1). The apparent volume of distribution at steady state (Vdss) was similar in the two groups. No significant difference in elimination half-life was observed between the two groups. Propofol was extensively bound (mean: 97-98%) to the plasma protein of both cirrhotic and control groups. This study shows that propofol pharmacokinetics and protein binding of propofol following a single intravenous bolus dose were not markedly affected by uncomplicated cirrhosis of the liver.

Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism.

Abstract: Recombinant human tumor necrosis factor (rH-TNF) is a cytotoxic monokine with pleiotropic effects. A phase I trial of rH-TNF was initiated using a five-day continuous intravenous (IV) infusion repeated every 28 days. Thirty-eight courses of therapy were administered to 19 patients. The starting dose was 5 X 10(4) U/m2/d, with escalations to 1.0 X 10(5), 2.0 X 10(5), 2.4 X 10(5), and 3.0 X 10(5) U/m2/d. Systemic side effects, including fever, chills, hypotension, fatigue, anorexia, and headaches, were mild and self-limiting. At the maximum tolerated dose of 3.0 X 10(5) U/m2/d, dose-limiting hematologic toxicity was manifested by transient thrombocytopenia and leukopenia. Elevated bilirubin levels were also seen at the higher dose levels. Lipoprotein analysis demonstrated that the five-day treatment with rH-TNF was associated with decreases in high-density lipoproteins, as well as increases in triglycerides and very-low-density lipoproteins. Pharmacokinetic studies using an enzyme-linked immunosorbent assay...

Pharmacokinetics and metabolism of epidoxorubicin and doxorubicin in humans.

Abstract: Pharmacokinetics of doxorubicin (DOX), epidoxorubicin (EPI), and their metabolites in plasma have been performed in eight patients receiving 40 to 56 mg/m2 of both anthracyclines as a bolus injection in two sequential cycles. Terminal half-life and volume of distribution appeared to be smaller in case of EPI, whereas plasma clearance and cumulative urinary excretion was larger in comparison to DOX. The major metabolite of DOX was doxorubicinol (Aol) followed by 7-deoxy-doxorubicinol (7d-Aolon). Metabolism to glucuronides was found in case of EPI only. The area under the curves (AUC) of the metabolites of EPI decreased in the order of the glucoronides E-glu greater than Eol-glu, 7d-Aolon greater than epirubicinol (Eol). The AUC of Eol was half of the value in its counterpart Aol. In the case of EPI, the AUC of 7d-Aolon was twice the level of that of the corresponding metabolite of DOX. The terminal half-lives of the cytostatic metabolites Aol and Eol were similar, but longer than the corresponding values of their parent drugs. Half-lives of the glucuronides (E-glu, Eol-glu) were similar to the half-life of their parent drug. 7d-Aolon had a somewhat shorter half-life in comparison to both DOX and EPI. Approximately 6.2% of EPI and 5.9% of DOX were excreted by the kidney during the initial 48 hours. Aol was found in the urine of patients treated with DOX, whereas Eol, E-glu, and Eol-glu were detected in urine of patients treated with EPI. The cumulative urinary excretion appeared to be 10.5% for EPI and its metabolites, and 6.9% for DOX and its metabolite. The plasma concentration v time curves of (7d)-aglycones showed a second peak between two and 12 hours after injection, suggesting an enterohepatic circulation for metabolites lacking the daunosamine sugar moiety. The plasma concentrations of the glucuronides were maximal at 1.2 hours for E-glu and 1.9 hours for Eol-glu. All other compounds reached their maximum plasma concentration during the first minutes after the administration of DOX and EPI. Deviating plasma kinetics were observed in one patient, probably due to prior drug administration.

Doxorubicin clearance in the obese.

Abstract: A study was carried out to examine the effect, if any, of obesity on doxorubicin pharmacokinetics. Body weight was found to be significantly related to doxorubicin clearance (r = -.75; P less than .001) and elimination half-life (r = .62; P = .003). Thus, the contribution of obesity on pharmacokinetics of antineoplastic agents should be taken into consideration in the analysis of clinical data with respect to toxicity and tumor response. Twenty-one patients were studied with their first course of doxorubicin (50 to 70 mg/m2) administered as a 60-minute intravenous (IV) infusion. Patients were divided into three groups on the basis of percentage of ideal body weight (IBW): normal (less than 115% IBW), mildly obese (115% to 130% IBW), and obese (greater than 130% IBW). Blood samples were collected up to 48 hours after the infusion and analyzed for doxorubicin and its metabolite, doxorubicinol, by high performance liquid chromatography. Doxorubicin area under the curve (AUC) was greater in obese than in norm...

Comparison of nasal, rectal, buccal, sublingual and intramuscular insulin efficacy and the effects of a bile salt absorption promoter.

Abstract: The purpose of this investigation was to develop a method to quantitate insulin absorption, and to compare insulin absorption from various noninjection sites of administration. Log dose/effect curves were established for i.m. insulin in adult male rats. The effects measured were the maximum change in plasma glucose concentration and the cumulative percentage of change in plasma glucose concentrations from 0 to 4 hr. Both log dose/effect curves gave similar results when calculating the efficacy of other routes, relative to i.m. Nasal, buccal, sublingual and rectal absorption sites were isolated by ligation procedures or with physical barriers. Rectal insulin was more efficacious than nasal, buccal and sublingual insulin, when administered without an absorption-promoting adjuvant. However, the efficacy relative to i.m. insulin was low for each route, probably due to a combination of slow membrane permeation and metabolism at the absorption site. Administration in a solution containing 5% sodium glycocholate, an absorption-promoting adjuvant, increased insulin efficacy by each route. The rank order was nasal greater than rectal greater than buccal greater than sublingual, with nasal and rectal insulin being roughly half as efficacious as i.m. insulin. Orally administered insulin, at doses 5 times higher than administered by other routes, and with Na glycocholate, produced no hypoglycemic response.

Clinical pharmacokinetics of carboplatin.

Abstract: The pharmacokinetics of carboplatin were investigated in cancer patients after single, IV infusion doses of 75, 150, 247.5, 300, 375, and 450 mg/m2. Total plasma and urine platinum and plasma ultrafilterable platinum concentrations were determined by atomic absorption spectrometry. Carboplatin was analyzed in plasma by a specific high-performance liquid chromatography (HPLC) procedure. Total plasma platinum, which represented free carboplatin, protein-bound platinum and metabolites, declined triexponentially; plasma half-lives (t1/2 lambda 1, 0.2 to 0.4 hr; t1/2 lambda 2, 1.3 to 1.7 hr; t1/2 lambda 3, 22 to 40 hr) and total body clearance (CLTB 2.8 +/- 0.5 L/m2/hr) were dose independent. Maximum plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) increased proportionally with dose. Plasma ultrafilterable platinum and carboplatin concentrations at doses of 375 and 450 mg/m2 declined in a biphasic manner. Plasma carboplatin elimination (t1/2 lambda 1, 0.50 hr; t1/2 lambda 2, 2.2 hr) and CLTB (4.4 to 5.6 L/m2/hr) were also independent of dose; AUC and Cmax increased proportionally to dose. Plasma free platinum was essentially all carboplatin for 8 or 12 hours after administration. Carboplatin did not bind to plasma protein in vitro but did degrade (t1/2-26 hours) to yield a reactive intermediate that bound rapidly and irreversibly to protein. The long terminal elimination half-life of plasma platinum was associated with irreversible binding of a platinum metabonate to plasma protein. The urinary excretion of platinum (0 to 24 hours) accounted for 58 to 72% of doses in 12 to 24 hours. The remainder of the dose is slowly excreted. The pharmacokinetics, in vivo stability, protein binding, and elimination of carboplatin are distinct from the first-generation analog cisplatin.

Optimization of cyclosporine therapy in renal transplantation by a pharmacokinetic strategy.

Abstract: Although cyclosporine (CsA) displays high immunosuppressive efficacy due to potent selective inhibition of T cell, but not nonspecific, immune functions, the pleiotropic toxicities of the drug result in a low therapeutic index. Thus for a given individual there is at best only a narrow dosage range producing immunosuppression not beclouded by toxicity. Selection of the appropriate CsA dose to achieve this state is complicated by marked inter- and intraindividual variability in drug pharmacokinetics and pharmacodynamics (1). Even considering renal transplant recipients solely, pharmacokinetic variations in drug absorption, volume of distribution, and metabolism as estimated by clearance rates are so great that strategies based on median population values are not useful for a great proportion of patients. Thus it is necessary to devise a CsA strategy that tailors therapy to compensate for interindividual variations. Implementation of such a strategy not only standardizes drug therapy, but also reveals the clinical impact of interindividual differences in the profile of CsA metabolites and in pharmacodynamic effects of a given quantity of CsA, reflecting both the therapeutic actions on the immune system and toxic effects on target organs. Thus a dosing strategy that achieves uniform drug levels by compensating for pharmacokinetic variation is essential for the eventual dissection of a rational CsA regimen.

Clinical pharmacokinetics of amantadine hydrochloride.

Abstract: Amantadine is a drug with diverse uses ranging from prevention of influenza A illness to the treatment of patients with Parkinson’s disease. It is available only in oral formulations from which it is well absorbed and widely distributed, little drug being present in the circulation. Apparent volume of distribution is inversely related to dose over the therapeutic range and accounts in part for a noteworthy logarithmic increase in plasma concentration as a function of dose. Elimination is primarily by renal clearance by both glomerular filtration and tubular secretion.

Pharmacokinetics of antimony during treatment of visceral leishmaniasis with sodium stibogluconate or meglumine antimoniate.

Abstract: 5 patients with visceral leishmaniasis were treated with sodium stibogluconate (2 patients) or meglumine antimoniate (3 patients) given intramuscularly at a dose of 10 mg antimony (Sb) per kg body weight daily for 30 d. Blood samples were obtained at intervals during treatment and blood Sb concentrations measured by anodic stripping voltametry. The pharmacokinetics of both drugs were remarkably similar, with peak concentrations of approximately 10 mg/litre occurring 2 h after the initial dose. Most of the Sb was eliminated rapidly, but nadir Sb concentrations increased gradually during treatment from 0·04-0·08 mg/litre 24 h after the first dose to 0·19-0·33 mg/litre 24 h after the 30th dose. For both drugs, the data were best described by a two compartment, three term pharmacokinetic model representing an initial absorption phase with a mean half-life of 0·85 h, a rapid elimination phase with a mean half-life of 2·02 h, and a slow elimination phase with a mean half-life of 76 h. The slow terminal elimination phase may be related to in vivo conversion of pentavalent Sb to trivalent Sb, which could contribute to the toxicity associated with long-term, high dose therapy.

Principles of drug biodisposition in the neonate. A critical evaluation of the pharmacokinetic-pharmacodynamic interface (Part II)

Abstract: Rational pharmacotherapy is dependent upon an understanding of the clinical pharmacokinetic and pharmacodynamic properties of the drugs employed. Although the available data on drug biodisposition and action in the neonate have increased considerably in the last few years, pharmacokinetic-pharmacodynamic interactions for many drugs remain poorly understood. The ontogeny of drug absorption, distribution, metabolism, and elimination are addressed in this review. Drug absorption from any site depends upon both the physicochemical properties of the drug and a variety of patient factors. Absorption of orally administered drugs may be affected by changes in gastric acidity and emptying time as well as by bile salt pool size, bacterial colonisation, and extraintestinal disease states such as congestive heart failure. Factors affecting drug absorption following intramuscular, percutaneous, and rectal administration are also discussed. Drug distribution in the neonate is influenced by a variety of important and predictable age-dependent factors. The developmental aspects of protein binding and body water compartments are described. Additionally, hepatic drug metabolism assumes an important role in understanding the pharmacokinetic and pharmacodynamic properties of many compounds. Certain biotransformation pathways, including hydroxylation by the P450 mono-oxygenase system and glucuronidation, demonstrate only limited activity at birth, while other pathways, such as sulphate or glycine conjugation, appear very efficient at birth. Elimination of drugs excreted unchanged in the urine is dramatically reduced in the newborn, compared with older infants and children, due to immaturity of both glomerular filtration and tubular secretory processes. The glomerular filtration rate remains markedly reduced prior to 34 weeks gestational age, increasing as a function of post-conceptual age until adult values are achieved by approximately 2.5 to 5 months of age. Tubular secretory capacity is also limited at birth, approaching adult values by approximately 7 months of age. Published reports describing the pharmacokinetics and pharmacodynamics of commonly used drugs in the neonatal period, as well as differences in drug biodisposition among premature infants, full term neonates, and older infants and children, are reviewed. Our recommendations for neonatal drug therapy are based upon a critical interpretation of these data, an understanding of fetal development and maturational processes, and an understanding of how disease states may affect drug biodisposition in the neonate.

The antithrombotic activity and pharmacokinetics of enoxaparine, a low molecular weight heparin, in humans given single subcutaneous doses of 20 to 80 mg.

Abstract: The pharmacokinetics of enoxaparine, a low molecular weight heparin, was randomly studied in 12 healthy male volunteers. Doses of 20, 40, 60, and 80 mg were injected subcutaneously in randomized cross-over fashion. Anti-IIa and anti-Xa activities (using amidolytic methods), and calcium thrombin time, were measured over 36 hours. The maximum Amax of the anti-IIa and anti-Xa activities appeared 3 to 4 hours after administration. The terminal half-lives of anti-IIa and anti-Xa activities were approximately 2 and 4 hours, respectively, with no significant variation between the different doses. For the anti-Xa activity, there was a highly significant positive correlation between the dose injected and individual values of Amax (r = +0.915; P less than .001) and AUC (r = +0.913; P less than .001). Enoxaparine displays a relatively small apparent volume of distribution (about 7.0 L) and its total body clearance is about 1.25 L/hr. The mean residence time ranges from 4.6 to 7.6 hours. Thus, the pharmacokinetic profile of enoxaparine is characterized by a linear relationship between dose and absorption, a relatively low clearance and long elimination half-life, and a high anti-Xa/anti-IIa ratio.

Fluconazole Penetration into Cerebrospinal Fluid: Implications for Treating Fungal Infections of the Central Nervous System

Abstract: Progress in the treatment of systemic mycoses in immunocompromised patients has been greatly impeded by the paucity of new, effective antifungal compounds. The need for such compounds, particularly agents that effectively penetrate the blood-brain barrier, has become even more important with the advent of AIDS, in which there is a 6V0-8V0 frequency of cryptococcosis of the CNS [1-3]. Cryptococcal meningoencephalitis in other populations of patients will generally respond to a treatment course of amphotericin B and flucytosine [4]. Courses of similar duration in patients with AIDS who have cryptococcal meningoencephalitis are, however, associated with a recurrence rate of ^O^o or with persistence of infection. Moreover, the toxicity of flucytosine in patients with AIDS often precludes an extended treatment course with this compound [2]. The need for extended and, perhaps, lifelong therapy with amphotericin B to prevent relapse of cryptococcosis of the CNS has recently been recognized [1, 3]. Fluconazole is a new triazole antifungal agent that has unique pharmacokinetic and pharmacological properties. The bioavailability after oral administration in humans is 80^0 [5]. Fluconazole has been shown to be effective in treating cryptococcal meningitis in animal models [6, 7] and has been proposed as a therapeutic alternative to long-term therapy with amphotericin B in patients with AIDS who have cryptococcal meningoencephalitis [8]. For human and subhuman primates, no pharmacokinetic data exist, however, that examine simultaneous sequential CSF and plasma levels of fluconazole to document and characterize penetration of this drug into the CSF. The current study was performed to evaluate CSF penetration of fluconazole by using a subhuman primate model that reliably predicts CSF penetration and pharmacokinetics of drugs in humans and has been demonstrated to serve as a valid substitute for human experimentation [9, 10].

A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine following intravenous administration to healthy volunteers.

Abstract: 1. The pharmacokinetics of hydroxychloroquine were studied in five healthy volunteers following an intravenous infusion of 155 mg (2.47 +/- 0.25 mg kg-1) racemic hydroxychloroquine. Four of these volunteers also received a further 310 mg (4.92 +/- 0.45 mg kg-1) infusion of hydroxychloroquine and evidence of nonlinearities in the pharmacokinetics of hydroxychloroquine were sought. 2. No nonlinear elimination or distribution processes appeared to be operating at the doses of hydroxychloroquine used in this study, supporting the hypothesis that in the therapeutic dosing range the pharmacokinetics of hydroxychloroquine are linear. 3. Half-life and mean residence time were long (around 40 days) and large volumes of distribution were calculated (5,522 l from blood, 44,257 l from plasma). Sequestration into the tissues is an important feature of the disposition of hydroxychloroquine. The persistence of hydroxychloroquine in the body is due primarily to this extensive tissue distribution, rather than to low clearance (667 ml min-1 based on plasma data, 96 ml min-1 based on blood data). 4. Plasma data were more variable than blood data. Blood to plasma concentration ratios were not constant (mean +/- s.d.: 7.2 +/- 4.2). The data indicate that it is preferable to measure whole blood concentrations of hydroxychloroquine, rather than plasma concentrations, in pharmacokinetic studies. 5. The pharmacokinetics of hydroxychloroquine are similar to those of chloroquine.

Phase I trial of multiple large doses of murine monoclonal antibody CO17-1A. II: Pharmacokinetics and immune response

Abstract: Twenty-five patients with metastatic gastrointestinal adenocarcinoma received one to four infusions of large doses (400 mg) of murine monoclonal antibody CO17-1A (17-1A). The pharmacokinetics of 17-1A at the time of first, second, third, or fourth infusion were not statistically different; plasma half-lives were 15.0 +/- 1.7 hours (n = 5), 15.1 +/- 1.8 (n = 10), 25.3 +/- 6.2 (n = 3), and 14.4 +/- 1.8 (n = 5), respectively. Most patients had an antibody response to 17-1A, with peak levels occurring 15-22 days after infusion. The presence of serum antibody to 17-1A at the time of the second or third infusion did not significantly alter the pharmacokinetics of this large dose of antibody. Four of 25 patients failed to develop an antibody response, but this did not correlate with the amount of 17-1A administered. The administration of four doses of 400 mg over 1 week provided continuously circulating 17-1A for 10 days.

The metabolism and pharmacokinetics of amlodipine in humans and animals.

Abstract: The disposition of amlodipine, a new calcium-channel blocker with a slow onset and long duration of action, has been investigated in humans and in the animal species used in the evaluation of drug efficacy and safety. Pharmacokinetic studies were conducted with nonlabeled drug using specific high-pressure liquid chromatography or gas chromatographic procedures. The metabolic fate of the drug was investigated in mice, rats, dogs, and humans using [4-14C]-amlodipine. After intravenous administration, the percentages of the dosed radioactivity recovered in urine were 62% in humans, 45% in dogs, 38% in rats, and 25% in mice. The remainder of the doses were recovered in the feces. A similar pattern of excretion was observed after oral dosing indicating complete absorption of the 14C drug. Absorbed drug is extensively metabolized because only approximately 5% of the dose was excreted unchanged in human urine. Metabolism in humans primarily involves oxidation to the pyridine derivative with subsequent oxidative deamination of the 2-aminoethyoxymethyl side chain or deesterification at the 5-methoxycarbonyl group. These metabolites were common to either the rat or dog, although some dihydropyridine derivatives were observed as metabolites in these two species. None of the metabolites identified and then synthesized was found to have any significant calcium antagonist activity relative to amlodipine. Bioavailability of unchanged drug after oral administration was high with values of 63, 88, 100, and 100% in humans, dogs, mice, and rats, respectively. Mean plasma half-life values from single-dose studies were 35 h in humans (cf nifedipine, approximately 2 h), 30 h in dogs, 3 h in rats, and 11 h in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Pharmacology of NSAIDs

Abstract: All nonsteroidal anti inflammatory drugs (NSAIDs) are characterized by a high degree of protein binding and small volumes of distribution. Differences in clearance account for the variability in half-life among these drugs. The majority are metabolized by the liver through a variety of pathways. These drugs are subject to drug interactions of several mechanisms, including protein-binding-displacement interactions, induction or inhibition of hepatic drug metabolism, and competition for active renal tubular secretion with other organic acids. NSAIDs are also subject to special pharmacokinetic considerations about which a great deal has been learned recently. These include data demonstrating that assessment of disposition of these drugs using only total drug concentrations can be misleading and that one must instead assess the disposition of unbound, pharmacologically active drug. Second, it appears that only one enantiomer of the propionic acid NSAIDs is active; studies of the pharmacokinetics of this class of NSAID should include assessment of the active stereoisomer. Finally, the propionic acid NSAIDs are metabolized to acyl-glucuronide conjugates, which are unstable and can cleave back to the parent drug. This feature allows the paradox of a drug that is metabolized by the liver being able to accumulate in patients who have renal insufficiency. Because of these newer pharmacokinetic considerations, much of the old data concerning the clinical pharmacology of NSAIDs are obsolete. More precise new information is needed in this area.

Pharmacokinetics of captopril in healthy subjects and in patients with cardiovascular diseases

Abstract: Captopril, the first orally active inhibitor of angiotensin-converting enzyme, is used widely in the treatment of hypertension and congestive heart failure. The pharmacokinetics of this agent have been studied extensively in healthy subjects and in patients with hypertension, congestive heart failure, and chronic renal failure. Captopril contains a sulphydryl group and binds readily to albumin and other plasma proteins. The drug also forms mixed disulphides with endogenous thiol-containing compounds (cysteine, glutathione), as well as the disulphide dimer of the parent compound. These components in blood and urine are measured collectively as total captopril. Because of the reversibility of the formation of these inactive disulphides, total captopril may serve as a reservoir of the pharmacologically active moiety, and thus contribute to a duration of action longer than that predicted by blood concentrations of unchanged captopril. To measure free or unchanged captopril concentrations, a chemical stabiliser must be added to the biological samples to prevent the formation of captopril disulphides ex vivo. In healthy subjects given captopril intravenously, the body clearance of captopril and steady-state volume of distribution were about 0.7 L/h/kg and 0.8 L/kg, respectively. The elimination half-life of unchanged captopril was approximately 2 hours. The primary route of elimination of captopril is the kidney. The renal clearance of unchanged captopril exceeds the glomerular filtration rate, due to active tubular secretion of the drug. In healthy subjects, about 70 to 75% of an oral dose is absorbed and the bioavailability of captopril is approximately 65%. Peak blood concentrations are reached about 45 to 60 minutes after oral administration. The bioavailability of captopril is not altered by age or concomitant medications including diuretics, procainamide, allopurinol, cimetidine or digoxin. However, the co-administration of food or antacids, or probenecid with captopril has been shown to diminish the bioavailability of the latter and decrease its clearance, respectively. The decreased bioavailability of captopril when taken with meals does not significantly alter clinical responses to the drug. Over a wide range of oral (10 to 150mg) and intravenous doses (2.5 to 10mg) captopril had linear kinetics in healthy volunteers. In healthy subjects with normal renal function and patients with congestive heart failure given captopril 3 times daily, blood concentrations of total captopril accumulated, whereas those of unchanged captopril did not. Severe renal insufficiency was associated with an accumulation of both unchanged and total captopril. In healthy subjects or hypertensive patients with normal renal function, urinary elimination of the drug is relatively rapid. Approximately 80% of an intravenous dose was recovered in the urine within 6 hours and about 50% of an oral dose was excreted in the first 4 hours after dosing. Urinary excretion of the parent drug accounted for about 35 to 40% of the dose, captopril disulphide about 5% of the dose, and the remainder was attributable to other metabolites, primarily captopril-cysteine mixed disulphide. Small amounts of S -methyl captopril have also been identified in plasma and urine.

Vancomycin concentrations in infected and noninfected human bone.

Abstract: Concentrations of vancomycin in bones of 14 patients undergoing total hip arthroplasty (group 1) and 5 patients with osteomyelitis (group 2) were studied. Group 1 received vancomycin, 15 mg/kg intravenously, 1 h prior to anesthesia. Group 2 received doses adjusted to achieve peak levels in serum of 20 to 30 micrograms/ml and trough levels of less than 12 micrograms/ml; bone specimens were collected during surgical debridement. The specimens were pulverized and eluted into phosphate buffer, and the supernatants were analyzed for vancomycin content by fluorescence polarization immunoassay. In group 1, vancomycin was detectable in all cancellous specimens with a mean concentration of 2.3 +/- 4.0 micrograms/g (range, 0.5 to 16 micrograms/g); 10 of 14 cortical specimens had detectable vancomycin; the mean cortical concentration was 1.1 +/- 0.8 micrograms/g (range, not detectable to 2.6 micrograms/g). In group 2, vancomycin was detectable in only two of five cortical bone specimens (mean concentration, 5.9 +/- 3.5 micrograms/g). Cancellous bone was obtained in one patient; the vancomycin concentration was 3.6 micrograms/g. In most patients the vancomycin levels in bones were higher than the MIC for susceptible staphylococci following single prophylactic doses. In the few infected patients studied, penetration was variable and deserves further study.

Pharmacokinetics of 5-Fluorouracil Assessed with a Sensitive Mass Spectrometric Method in Patients on a Dose Escalation Schedule

Abstract: The pharmacokinetics of 5-fluorouracil (5-FUra) was investigated in 21 patients with advanced cancer (mainly colorectal cancer). 5-FUra was administered as weekly i.v. bolus injections usually at a starting dose of 500 mg/m2. Every 4 weeks the dose was escalated by 20% until dose-limiting toxicity was observed. Whenever possible, pharmacokinetic studies were performed at dose escalation. 5-FUra plasma concentrations were measured by high pressure liquid chromatography and a sensitive gas chromatography-mass spectrometry assay with a sensitivity as low as 3 x 10(-9) M. According to the 42 plasma concentration versus time curves, in all but one of the patients total body clearance decreased with increasing 5-FUra doses, consistent with the nonlinear pharmacokinetics of 5-FUra. The ultrasensitive assay revealed an almost horizontal phase in the plasma concentration versus time curves at plasma concentrations of 10(-8) to 10(-9) M. This plateau did not show correlation with the area under those curves. The use of a logistic regression method showed that clinical toxicity was correlated with the area under the plasma concentration versus time curve of 5-FUra.

The pharmacokinetics of oxybutynin in man.

Abstract: We have studied the pharmacokinetics of oxybutynin (Ditropan) after single oral (5 mg) and intravenous administration (1 and 5 mg), and after repeated oral administration in healthy volunteers

Clinical pharmacokinetics in heart failure. An updated review.

Abstract: Pharmacokinetics is the study of the effect that the body has on drug absorption, distribution, metabolism and excretion. The pharmacokinetics of a specific drug are assessed by the volume of distribution, bioavailability, clearance and elimination half-life. Elimination half-life is directly related to the volume of distribution and inversely related to clearance. Any 1 or more of these parameters may be altered by physiological changes such as ageing, or disease states such as congestive heart failure. Congestive heart failure is associated with hypoperfusion to various organs including the sites of drug clearance, i.e. the liver and kidneys. It also leads to organ congestion as seen in the liver and gut. The main changes in drug pharmacokinetics seen in congestive heart failure are a reduction in the volume of distribution and impairment of clearance. The change in elimination half-life consequently depends on whether both clearance and the apparent volume of distribution change, and the extent of that change. Pharmacokinetic changes are not always predictable in congestive heart failure, but it seems that the net effect of reduction in the volume of distribution and impairment of clearance is that plasma concentrations of drugs are usually higher in patients with congestive heart failure than in healthy subjects. The changes in pharmacokinetics assume importance only in the case of drugs with a narrow therapeutic ratio (e.g. digoxin) and some of the antiarrhythmics such as lignocaine (lidocaine), procainamide and disopyramide. This necessitates reduction in both the loading and maintenance doses. Prolongation of the elimination half-life leads to delay in reaching steady-state, and therefore dose increments must be made more gradually. Plasma concentration measurements of the drugs concerned are a good guide to therapy and help to avoid toxicity. Pharmacokinetic changes are of less importance in the case of drugs with immediate clinical response, e.g. diuretics and intravenous vasodilators such as nitrates and phosphodiesterase inhibitors. The dose in the latter group can be titrated to the desired effect. Not all adverse reactions to drugs that may occur in heart failure are the result of alterations in pharmacokinetics; rather, some may be due to important drug interactions. An interaction may occur directly e.g. reduction of renal clearance of digoxin by captopril and quinidine; or indirectly, e.g. through diuretic-induced hypokalaemia, which exacerbate arrhythmias associated with digoxin and antiarrhythmics such as quinidine and procainamide.

Pharmacokinetics of fentanyl in neonatal humans and lambs: effects of age.

Abstract: To determine whether the clearance of fentanyl in neonates varies with age, the authors determined the pharmacokinetics of fentanyl in 14 humans ages 1-71 days and 15 lambs ages 3-37 days. In humans, fentanyl, 54.1 +/- 2.3 (mean +/- SD) micrograms/kg, was administered as a 2-min iv infusion; in lambs, fentanyl, 50 micrograms/kg, was administered as an iv bolus. Ventilation was controlled to maintain end-tidal or arterial PCO2 normal, and potent inhaled anesthetics were not administered; in humans, additional anesthesia was provided with iv morphine. Arterial or venous samples were obtained for 12 h, and plasma concentrations of fentanyl were determined by radioimmunoassay. Plasma concentration versus time data were fitted to two- and three-compartment pharmacokinetic models, and clearance, volume of distribution at steady-state (Vdss), and elimination half-life were determined. Clearance increased with age in both humans and lambs. Two humans who had intraabdominal surgery had no clearance of fentanyl: plasma concentrations of fentanyl remained constant for approximately 10 h after an initial distribution phase. In lambs, but not in humans, Vdss increased with age; elimination half-life did not change with age in either lambs or humans. The authors conclude that at least two factors--postnatal age and the type of surgery--affect fentanyl clearance during the neonatal period. The effect of other factors, such as inhaled anesthetics, remains to be determined.

Circadian changes in the pharmacokinetics and cardiovascular effects of oral propranolol in healthy subjects.

Abstract: Four subjects were synchronized with activity from 07 to 23 h and were given a single oral dose of 80 mg racemic propranolol at fixed times (08, 14, 20 and 02 h) at weekly intervals. ANOVA revealed significant circadian changes in the peak propranolol concentration (Cmax), with a maximum at 08 h and a minimum at 02 h after drug intake; tmax was not dependent on the circadian phase. The elimination half-life varied significantly with the time of day, being shortest at 08 h (3.3 h) and longest at 20 h (4.9 h). The stereospecificity of the propranolol pharmacokinetics was not dependent on the time of drug intake. No circadian variation was found in the maximum decrease in heart rate, but the time to peak effect was dependent on the time of drug intake; tmax was 2.3 h at 08 h and 7.0 h at 02 h. Thus, the time to peak drug concentration did not coincide with the time to peak effect on heart rate at different times of day. Circadian changes were also found in the systolic blood pressure and in the double product. The results show a significant daily variation in the pharmacokinetics and cardiovascular effects of propranolol. However, chronokinetics cannot explain the circadian changes in the effects of the drug. It is concluded that circadian variation in sympathetic tone and vascular reactivity is mainly responsible for the circadian changes in the effects of propranolol.

Stereoselective pharmacokinetics of ketoprofen in the rat. Influence of route of administration.

Abstract: The 2-arylpropionic acid nonsteroidal anti-inflammatory drugs are usually administered as racemates. The enantiomers may have different pharmacokinetics and the R-isomer may metabolically invert to the S-isomer. To pinpoint the kinetics of the inversion and the location in which this metabolic process takes place, racemic ketoprofen (KT) was administered to the rat. Using a stereospecific HPLC assay, the pharmacokinetics of KT were studied following 10 mg/kg iv, po, and ip doses of racemic KT to male Sprague-Dawley rats. Plasma concentrations were always greater for (S)-KT than for (R)-KT. The mean +/- SD AUC S/R ratios were 11.8 +/- 9.93 (N = 5), 11.0 +/- 2.64 (N = 4), and 33.7 +/- 11.2 (N = 5) after iv, ip, and po doses, respectively. Bile duct-cannulated rats (N = 4) had AUCs of 85.4 +/- 58.6 and 22.8 +/- 18.4 (mg/liter) hr for (S)- and (R)-KT, respectively. The percentage of conjugated drug recovered in bile was 77.9 +/- 3.77 and 11.4 +/- 2.48% of the dose as (S)- and (R)-KT, respectively. The data indicate 1) substantial stereoselectivity, 2) presystemic gastrointestinal and systemic inversion of (R)- to (S)-KT, 3) extensive elimination of drug through bile in rats, and 4) extensive reabsorption subsequent to biliary excretion.