Drug Elimination Rate Research Articles

Age and the Metabolism of Drugs

Many factors contribute to the altered responsiveness of the elderly to drug therapy [1]. Of these, particular attention has been given to investigating the effect of age upon the rate of drug elimination since, unless appropriate reductions in dosage are made, significant age-related reductions in clearance will tend to lead to higher blood levels, and hence a greater risk of toxicity [2]. The effects of age on renal drug clearance are now well-documented [3-5], and parallel the decline in renal function which occurs in the elderly. Physicians are thus accustomed to matching the dosages of drugs which undergo renal excretion to elderly patients' renal function. In many instances, serum creatinine levels alone provide sufficient guide to appropriate doses although, for drugs with low therapeutic ratio, it may be necessary to measure plasma drug levels to avoid toxicity. Age-related changes in the rates of drug metabolism have also been reported for many common therapeutic agents. Unfortunately, no clear pattern has emerged, and those changes that do occur are superimposed on .the wide range of genetic and environmental factors known to influence rates of drug metabolism. Two general trends have emerged: first, and with some notable exceptions, drugs undergoing hepatic microsomal oxidation are likely to be metabolised more slowly in the elderly, whilst those that are conjugated are usually uninfluenced by age; second, drugs with high hepatic clearances and extraction ratios (such as chlormethiazole and labetalol), and which undergo extensive 'first-pass', metabolism during oral absorption, may show substantially increased bioavailability in the elderly [2].

Comparative metabolism and elimination of adriamycin and 4'-epiadriamycin in the rat.

Adriamycin (ADR) and 4'-epiadriamycin (epi-ADR) show comparable biological properties in most in vitro and in vivo test systems. However, in animal studies epi-ADR demonstrates diminished toxicity, especially toward cardiac tissue, compared with ADR. A similar reduction in anthracycline-induced cardiotoxicity with epi-ADR, relative to ADR, is claimed in connection with the clinical evaluation of this agent. The present study was undertaken in an attempt to find a possible pharmacological basis for this observed differential toxicity. Following identical bolus doses (10 mg/kg) of drug administered to rats, no differences were seen in plasma drug levels of the two agents at 4, 7, and 24 h. However, differences in the rate and extent of drug elimination were clearly noted. Thus, following either 24-h infusion or bolus drug administration, parent drugs were eliminated largely in the bile, with the recovery of epi-ADR [50% (infusion) and 40% (bolus) in 54 h and 55 h respectively] exceeding that of ADR [31% (infusion) and 23% (bolus) at the corresponding times]. Recovery of a bolus drug dose in the urine was only 4.8% for epi-ADR vs 3.3% for ADR in 60 h. For each drug the only significant metabolite seen was the corresponding 13-carbinol derivative, adriamycinol (AMNOL) or 4'-epiadriamycinol (epi-AMNOL). The 13-carbinol metabolite represented a larger part of the recovered dose for ADR [15% (infusion) and 18% (bolus) in bile, 0.3% in urine] than for epi-ADR [7% (infusion) and 11% (bolus) in bile, 0.04% in urine]. Epi-ADR was found to be a four fold poorer substrate than ADR for conversion to its 13-carbinol metabolite by aldo-keto reductase enzymes in crude rat liver homogenate preparations. This latter finding provides an explanation for the metabolic and toxicologic differences observed with these agents in whole animals. Previous studies with ADR have reported that degenerative changes in rat cardiac tissue were accompanied by an accumulation of AMNOL during chronic drug administration. Thus, the present study suggests that the reported lower toxicity of epi-ADR compared to ADR for the heart may result from a more extensive elimination of parent drug in bile and urine, as well as diminished metabolic conversion to its 13-carbinol metabolite by ubiquitous aldo-keto reductase enzymes.

Development of acute tolerance to bumetanide: bolus injection studies.

Bumetanide was administered intravenously to four mongrel dogs, in a random crossover fashion, at doses of 0.05 mg/kg (I), 0.15 mg/kg (II), and 0.5 mg/kg (III) where urinary losses were replaced with lactated Ringer's solution at 1.5 ml/min (hydropenic conditions) or at a dose of 0.5 mg/kg (IV) where urinary losses were replaced with lactated Ringer's solution isovolumetrically (euvolemic conditions). Serial plasma and urine samples were assayed for bumetanide by high-performance liquid chromatography (HPLC) and for sodium by flame photometry. There were no significant differences in the pharmacokinetic parameters of bumetanide among Treatments I-IV. The dynamic parameters Emax (maximum effect attributable to the drug) and s (slope factor) were not different between treatments. However, a consistent, demonstrable increase in ER50 (urinary excretion rate of drug producing 50% of Emax) was observed among Treatments I (2.34 micrograms/min), II (3.92 micrograms/min), and III (6.54 micrograms/min); also, a significant decrease in ER50 was observed between Treatment III (6.54 micrograms/min) and Treatment IV (2.66 micrograms/min). These results show that hydration status has a marked effect on natriuretic and diuretic response and that tolerance can rapidly develop within a single intravenous dose of bumetanide.

Species Differences in Pharmacokinetics and Drug Teratogenesis

Interspecies differences in regard to the teratogenicity of drugs can be the result of differing pharmacokinetic processes that determine the crucial concentration-time relationships in the embryo. Maternal absorption, as well as distribution, of the drugs does not usually show great species differences. The first-pass effect after oral application is often more pronounced in animals than man (e.g., valproic acid, 13-cis-retinoic acid), although in some cases the reverse was found (e.g., hydrolysis of valpromide). Existing differences can be adjusted by appropriate choice of the administration route and measurements of drug levels. Many variables determine the placental transfer of drugs: developmental stage, type of placenta, properties of the drug. Even closely related drugs (e.g., retinoids) may differ greatly in regard to placental transfer. Maternal protein binding is an important determinant of placental transfer, since only the free concentration in maternal plasma can equilibrate with the embryo during organogenesis; this parameter differs greatly across species (e.g., valproic acid: five times higher free fractions in mouse and hamster than in monkey and man). The metabolic pattern has not yet been demonstrated to be a major cause of species differences, although recent evidence on phenytoin and thalidomide support the hypothesis that some species differences can be the result of differing activation/deactivation pathways. Laboratory animals usually have a much higher rate of drug elimination than man. Drastic drug level fluctuations are therefore present during teratogenicity testing in animals, but not to the same degree in human therapy. It must, therefore, be investigated if peak concentrations (such as for valproic acid and possibly caffeine) or the area under the concentration-time curve (AUC) (such as for cyclophosphamide and possibly retinoids) correlate with the teratogenic response. Only then is a rational and scientific basis for interspecies comparison possible. It is concluded that the prediction of the human response based on animal studies can be improved by consideration of the appropriate pharmacokinetic determinants.

Species differences in pharmacokinetics and drug teratogenesis.

Interspecies differences in regard to the teratogenicity of drugs can be the result of differing pharmacokinetic processes that determine the crucial concentration-time relationships in the embryo. Maternal absorption, as well as distribution, of the drugs does not usually show great species differences. The first-pass effect after oral application is often more pronounced in animals than man (e.g., valproic acid, 13-cis-retinoic acid), although in some cases the reverse was found (e.g., hydrolysis of valpromide). Existing differences can be adjusted by appropriate choice of the administration route and measurements of drug levels. Many variables determine the placental transfer of drugs: developmental stage, type of placenta, properties of the drug. Even closely related drugs (e.g., retinoids) may differ greatly in regard to placental transfer. Maternal protein binding is an important determinant of placental transfer, since only the free concentration in maternal plasma can equilibrate with the embryo during organogenesis; this parameter differs greatly across species (e.g., valproic acid: five times higher free fractions in mouse and hamster than in monkey and man). The metabolic pattern has not yet been demonstrated to be a major cause of species differences, although recent evidence on phenytoin and thalidomide support the hypothesis that some species differences can be the result of differing activation/deactivation pathways. Laboratory animals usually have a much higher rate of drug elimination than man. Drastic drug level fluctuations are therefore present during teratogenicity testing in animals, but not to the same degree in human therapy. It must, therefore, be investigated if peak concentrations (such as for valproic acid and possibly caffeine) or the area under the concentration-time curve (AUC) (such as for cyclophosphamide and possibly retinoids) correlate with the teratogenic response. Only then is a rational and scientific basis for interspecies comparison possible. It is concluded that the prediction of the human response based on animal studies can be improved by consideration of the appropriate pharmacokinetic determinants.

A Decade of Developments in Diuretic Drug Therapy

New diuretics introduced into clinical medicine during the past decade include potent new loop diuretics such as bumetanide and piretanide, the uricosuric indanyloxyacetic acid derivative indacrinone, and a new generation of sulfamoyl diuretics such as indapamide and xipamide, which are recommended primarily for the treatment of hypertension. Pharmacokinetic studies of individual diuretics have demonstrated that the diuretic and natriuretic responses to the newer agents generally follow the plasma drug concentration-time curves and urinary drug excretion rates. Therapeutic monitoring can therefore be achieved in most patients with edema or hypertension by close clinical observation and laboratory analysis of plasma electrolyte and creatinine concentrations and urinary electrolyte excretion rates. Interest in the mechanisms involved in the renal and extrarenal vascular actions of the newer diuretics has led to a better understanding of how changes in venous compliance, peripheral vascular resistance, and renal blood flow distribution may contribute to the overall therapeutic response to these agents, especially in patients with severe congestive heart failure, renal insufficiency with low glomerular filtration rates, and hypertension with cardiorenal complications. Adverse reactions to modern diuretics, which are mainly an extension of their renal pharmacodynamic effects, have proved to be minimal, provided that the dosage is adjusted to meet but not exceed individual patient requirements. However, the long-term consequences of prolonged periods of diuretic-induced alterations in plasma potassium levels, and metabolic effects that include elevated blood lipids, are still under investigation.

Reduction of paracetamol and aspirin metabolism during viral hepatitis.

The single-dose pharmacokinetics of two analgesic drugs, paracetamol (acetaminophen) and aspirin, were studied in healthy volunteers and in patients with viral hepatitis during the acute and the convalescent phase. Impaired elimination of paracetamol and aspirin was found in hepatitis patients, while plasma peak concentrations were unaffected. Recovered patients were not different from healthy controls in the rate of drug elimination. The data suggest normal single dosage for these drugs in acute viral hepatitis, and dosage modification only in severe cases.

Induction of cytochrome P-448 iso-enzymes and related glucuronyltransferases in the human liver by cigarette smoking.

Human liver 10-20 mg from biopsy samples removed for diagnostic purposes from selected patients has been used for the preparation of microsomes. The activity of certain mono-oxygenases and UDP-glucuronyltransferases, as well as certain other enzymes involved in drug metabolism, has been determined using different substrates as indicators. Smokers oxidized benzo(a)pyrene and 7-ethoxyresorufin and also conjugated alpha-naphthol at a significantly increased rate compared to non-smokers. This indicates induction of certain mono-oxygenases and glucuronyltransferases which differs from the induction produced by phenobarbital. The findings can account for the reduced activity and increased elimination rate of certain drugs prescribed to smokers.

The determination of mean residence time using statistical moments: it is correct.

The present communication seeks to end a controversy created by a recent publication regarding the applicability of statistical moment principles for determination of mean residence time of drug in the body tb. It is shown that the equation tb = AUMC/AUC is correct when applied to pharmacokinetic systems in which the total drug elimination rate is directly proportional to the drug concentration in the systemic circulation, i.e., first-order central elimination. More general equations for tb in terms of elimination rate, amount eliminated, and amount in the body are presented along with demonstrations of their utility.

Disposition of Pentopril, a New Orally Active Angiotensin-Converting Enzyme Inhibitor, and Its Active Metabolite in Rats

The disposition characteristics of pentopril (the ethyl ester) and its active carboxylic acid metabolite (CGS 13934) were determined in conscious rats after separate intravenous administrations of both compounds. The relationship between plasma concentration and pharmacological effect was also evaluated. The extent of apparent bioavailability of the active metabolite was determined after oral administration of pentopril. Pharmacokinetic parameters were calculated from the plasma concentration-time data for both the parent drug and its active metabolite after their separate intravenous administrations using a one-compartment model for the drug and a two-compartment model for the metabolite. The elimination half-life for the drug was ∼1min. The elimination half-life for the metabolite was 13min (SD, ±3.5, n equals; 4) after its direct intravenous administration, but increased to an apparent half-life of 20min (SD ±5, n equals; 5) when formed in vivo as a metabolite. Comparison of the formation rate of the metabolite and the elimination rate of the parent drug indicated that the parent drug was rapidly and completely hydrolyzed to the acid metabolite as soon as it reached the systemic circulation. No parent drug was detected in plasma after its oral administration. The apparent bioavailability of the acid metabolite was 66% after oral drug administration. A close relation between inhibition of pressor response to angiotensin I (AI) and plasma concentration of the active metabolite was observed when plotted against time after drug or metabolite administration. A Michaelis-Menten function correlated (multiple r2: 0.995) well between effect and plasma metabolite concentration with mean concentration for 50% of maximum inhibition, IC50, of 3.6 × 10−7 M (0.11 μg/mL).

Urinary Protein Binding, Kinetics, and Dynamics of Furosemide in Nephrotic Patients

The urinary protein binding, kinetics, and dynamics of furosemide were studied in five nephrotic patients after intravenous dosing. Serial plasma and urine samples containing furosemide were analyzed by HPLC, and drug binding to plasma and urinary proteins was determined using equilibrium dialysis techniques. In comparison to data reported previously in healthy subjects, the steady-state volumes of distribution and nonrenal plasma clearances were significantly increased in nephrotic patients, reflecting the reduced binding of furosemide to plasma proteins. Although there was no significant difference in renal clearance between these two groups, the unbound renal clearance of furosemide was significantly reduced in nephrotic patients even when compensated for by the number of functioning nephrons. Furosemide was extensively bound to urinary protein (19.6–78.4%), and the binding was dependent on the degree of proteinuria. Nevertheless, dose–response analyses, in which the response was represented by sodium excretion rate and the dose by urinary excretion rate of unbound drug, demonstrated that nephrotic patients were less responsive to equivalent amounts of unbound diuretic as compared to healthy subjects.

Clinical pharmacokinetics of changes in drug elimination in children.

This review mainly summarizes selected aspects of the present knowledge of drug elimination kinetics independent of developmental changes, with special attention given to clinical situations. The effects of different disease states, drug interactions, changes in urinary pH, induction of microsomal enzymes, competition for renal excretory mechanisms, possible enterohepatic recirculation, binding of drugs to tissues, effects of a drug on another drug's metabolizing organ, and dose-dependent elimination, on increase or decrease of drug elimination rates in children, have been presented. Based on the available data it seems that one may postulate the following conclusions: (1) that the distribution factors as well as changes in drug elimination capacities seem to play a role, perhaps with differing relative importance, during each of the maturational periods; (2) that the physicochemical properties of a drug and its dosage, as well as changes in the volume of distribution in children, in the course of certain disease states may have a significant effect on kinetics of drug disposition in the body; (3) that systemic clearance, a model independent parameter, rather than elimination half-life, a hybrid pharmacokinetic parameter, more accurately reflects elimination of some drugs from the body; (4) that each drug and every clinical situation may require the evaluation of the direct effect on pharmacokinetic processes, since general principles may not always apply; (5) that drug disposition studies should also be performed, if possible, on patients under actual clinical situations and receiving the usual therapeutic regime, and (6) that the half-life of colistin is independent of postnatal age which should serve as a warning not to generalize about drug excretion in the young infant.

Pharmacokinetics and comparative nephrotoxicity of fixed-dose versus fixed-interval reduction of gentamicin dosage in subtotal nephrectomized dogs

There is presently no consensus as to the relative safety of fixed-interval/reduced dose (FI) vs fixed-dose/increased interval (FD) dosage adjustment regiments for use in renal insufficiency. This study compared their nephrotoxic potential using gentamicin in beagle dogs with renal insufficiency secondary to subtotal surgical nephrectomy. Pharmacokinetic analysis in six dogs showed that this surgical procedure resulted in a decreased total body clearance of drug and a marginally contracted volume of the central compartment. An allometric analysis of gentamicin disposition in different species was used to derive a human-equivalent maximum canine nontoxic dose of 9 mg kg −1 day −1. Nephrotoxicity was detected by histopathologic analysis and changes in the pre- and post-drug treatment, creatinine clearance, and daily drug elimination rate constants. This allometric dose did not produce clinical toxicity in a control group of six dogs with intact kidneys given drug for 14 days. Dosage adjustments within the FI and FD groups were based on serum creatinine concentrations 10 days after surgery. Statistical analysis of morphological and functional parameters indicated that the FD method was significantly less toxic than the FI regimen.

Urinary Excretion of Chlorpheniramine and Its Metabolites in Children

The pharmacokinetics and urinary excretion of chlorpheniramine were studied in 11 patients, aged 6–16 years, with allergic rhinitis. In these children, chlorpheniramine had a mean elimination half-life of 13.1 ± 6.6 h, a mean clearance rate of 7.23 ± 3.16 mL/min/kg, and a mean apparent volume of distribution of 7.0 ± 2.8 L/kg. Over 48 h, the recovery in urine was as follows: chlorpheniramine, 11.3 ± 6.7%; demethylchlorpheniramine, 23.3 ± 11.1%; and didemethylchlorpheniramine, 9.6 ± 9.4%. Urine flow rate and urine pH were uncontrolled and ranged from 2.2 to 113.3 mL/h and 5.1-7.9, respectively, over the 48-h period. In some children urine flow rate and pH were constant, while in others there was great variability. When drug and metabolite excretion rates versus both urine flow rates and pH values were analyzed by multiple linear regression, the results were significantly better (p ± 0.05) than when each factor was analyzed independently. The excretion rate of chlorpheniramine and its two demethylated metabolites decreased as urine pH increased and urine flow rate decreased. This information must be considered in future pharmacokinetic studies of this drug.

Pharmacokinetics of intra-arterial tumour therapy. An experimental study.

Mathematically based pharmacokinetic models confirmed the general belief that intra-arterial (i.a.) cytostatic drug infusion can produce an increase in local tissue levels and a reduction in systemic drug availability. The increase in local drug concentration depends largely on the blood-flow rate of the infused artery and the rate of drug elimination from the rest of the body. In an experimental canine model the pharmacokinetics of i.a. infusion were studied using the femoral artery as the site of infusion and an Anger camera for continuous measurement of drug concentration in the target region. Several radioactively labelled drugs with different kinetics were infused over 80 min. The decay phase after the end of i.a. infusion was also monitored. The results indicate that even the femoral artery with its high blood flow is a suitable site for i.a. infusion, provided the plasma half-life of the drug is short enough. Consequently, arteries with lower blood flow (e.g., lingual artery) are even more suitable for i.a. infusion. The various diagrams obtained from this study provide a quick indication of whether or not a drug is suitable in a certain clinical situation.

The pharmacology of verapamil. V. Tissue distribution of verapamil and norverapamil in rat and dog.

The relative distribution of verapamil and its demethylated metabolite, norverapamil, was studied in rats at intervals after intraperitoneal injection of the parent drug (30 mg/kg). This route of drug administration simulated oral drug dosing, and the highest concentrations of both unchanged drug and metabolite were found in the liver, with lung and kidney containing most of the remainder. The rates of disappearance of verapamil from various organs followed first-order kinetics, and the most rapid elimination occurred from brain and liver. In contrast, verapamil was given intravenously to 3 dogs by a bolus-infusion method to produce sustained steady state plasma concentrations (80, 140, 250 ng/ml) for 1, 2, and 3 h. After systemic administration, the lungs contained almost half the tissue verapamil and, 20% was found in kidney, with the liver accounting for only 17%. Norverapamil was not found in plasma or brain. These studies contrast the pattern of tissue distribution of verapamil after different routes of drug administration. The variable rates of drug elimination from specific tissues may explain the differing durations of the drug's observed effects.

Pharmacokinetic considerations in the haemodialysis of drugs.

Clinical pharmacists can deliver safer and more efficacious drug therapy to end-stage renal patients with knowledge and application of the pharmacokinetics of haemodialysis. The physical, chemical and pharmacokinetic properties of a drug will determine its degree of dialysability. These properties included water solubility, molecular weight, protein binding, volume of distribution, and the fraction, route and rate of drug elimination. Various dialysis-induced metabolic alterations must also be considered. With an understanding of these factors, the pharmacist can determine whether dosage adjustments are necessary and, if so, make the required calculations accurately.

Determinants of the diuretic response to furosemide in infants with congestive heart failure.

A wide interindividual variation in the degree of diuresis produced following treatment with furosemide has been observed in infants with congestive heart failure. A method of pharmacokinetic analysis that separates drug disposition from renal response to furosemide was used to compare the effect of this agent in infants with congestive heart failure with the effect seen in infants with fluid retention secondary to noncardiac factors. No differences in the drug elimination rate, urinary drug excretion, or renal diuretic response between the 2 groups were seen. Infants in both groups exhibited a wide range in all variables examined. The marked interindividual variation in response originates from decreased delivery of furosemide to its site of action in some patients and a decreased responsiveness to the drug in others.

Clobazam kinetics: intrasubject variability and effect of food on adsorption.

The kinetics of single 20-mg oral doses of clobazam was determined on two occasions in 12 healthy male volunteers. Clobazam was given in the fasting state on one occasion and following a standard breakfast on another. Compared with the fasting state, administration of clobazam with food reduced mean peak plasma concentrations (465 vs. 333 ng/ml, P less than 0.01), and prolonged the time to reach peak concentration (1.7 vs. 2.5 hours after dosage, P less than 0.1). Total area under the curve nor the extent of formation of desmethylclobazam, the major metabolite. Clobazam AUC and elimination half-life each were highly correlated within subjects between the two trials (r = 0.97 and 0.95, respectively). Thus, administration of clobazam with food slows the rate of clobazam absorption but does not alter the completeness of absorption. The rate of drug elimination is highly replicable upon repeated administration clobazam to the same individual.

Pharmacokinetics of methyldopa in renal failure and bilaterally nephrectomized patients.

The elimination from plasma of 14C-labelled methyldopa was studied in three bilaterally nephrectomized patients and four patients with reduced renal function. The elimination of radioactivity was slow, particularly in the anephric patients where about 50% of the injected dose was still present in plasma after 48 hours. Chemically determined methyldopa disappeared from plasma much faster than radioactivity in both groups of patients, suggesting formation and retention of metabolite(s). The urinary excretion rate of both radioactivity and unchanged drug in the patients with renal failure was slow in comparison with normal subjects. Moreover, the composition of the 0–48 hour urine differed from that of normals, showing a lowered content of unchanged drug. Slow elimination of unidentified metabolite(s) might possibly explain the strong and prolonged hypotensive action of methyldopa in patients with renal failure.