Ethanol as a mobile-phase solvent in high-performance liquid-chromatographic assays.
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Acetonitriles↗
Biomedical subjects
R L Nation
Publications and source records attributed to R L Nation.
Gas chromatographic method for the quantitative determination of lidocaine and its metabolite monoethylglycinexylidide in plasma.
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Chromatography, Gas↗
The pharmacokinetics of chlormethiazole following intravenous administration in the aged.
Eight healthy aged subjects were administered 1.2 g of chlormethiazole by constant-rate intravenous infusion. The disposition of the drug was found to be multi-exponential in character. Fits of plasma level-time data to two- and three-compartment open models were assessed with the aid of statistical tests. For three of the subjects the experimental data were adequately fitted to a two-compartment pharmakcokinetic model, however a three-compartment model was necessary to fit the data observed for a further four subjects. An anomalous chlormethiazole plasma concentration-time curve was obtained for the remaining subject. The disposition half-life of chlormethiazole was 8.49 +/- 3.28 h and the plasma clearance was 16.14 +/- 5.00 ml/min/kg. These values were significantly different to those reported earlier for young adult subjects and the clinical implications have been discussed. The blood/plasma concentration ratio of chlormethiazole was found to be approximately one with some evidence for concentration dependence.
Aged↗
Pharmacokinetics in the elderly.
The pharmacokinetics of sulphamethizole, paracetamol and phenylbutazone were investigated and compared in young and geriatric subjects. The rate and extent of absorption of the drugs did not appear to be affected by increasing subject age. However, the mean half-lives for sulphamethizole and paracetamol were significantly increased in the geriatric subjects. A number of correlations are presented between the elimination rate constants of the drugs and certain subject parameters and variables. The elimination of phenylbutazone was found not to be influenced significantly by subject age. The apparent volumes of distribution of the three drugs were not age-dependent.
Acetaminophen↗
Pharmacokinetics in the aged: a review.
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Age Factors↗
The single-point method of dosage prediction: pharmacokinetic basis and method optimization.
Based on the principle of superposition an expression has been established relating a drug concentration at steady-state to a concentration after a single dose. This relationship applies for drugs with linear pharmacokinetics given at equal dosage intervals and it is independent of the route of administration. The relationship provides theoretical justification for the single-point method of dosage prediction reported in the literature. The test conditions in the method can therefore be optimized and the limits of the method defined. The expression can also be used for individualized prediction of maintenance dose after estimation of drug half-life in the patient with no limit to half-life values to which it can be applied.
Half-Life↗
The relationship between the pharmacokinetics of ibuprofen enantiomers and the dose of racemic ibuprofen in humans.
Ibuprofen is a chiral drug which is used clinically as a racemate. The pharmacological properties of ibuprofen reside almost exclusively with the S(+)-enantiomer. However, a portion of R(-)-ibuprofen is metabolically inverted to its pharmacologically active, mirror-image form. To investigate the influence of increasing dose of racemic ibuprofen on the pharmacokinetics of its individual enantiomers, four healthy male volunteers were given racemic ibuprofen (200, 400, 800, and 1200 mg), orally, on four occasions. The study was conducted using a balanced cross-over design. The extent of absorption of ibuprofen, as assessed by the total urinary recovery of ibuprofen and its metabolites, was extensive and independent of the administered dose. At all four doses, the area under the total and unbound plasma concentration-time curves (AUC and AUCu, respectively), and the unbound fraction in plasma, were significantly greater for the S(+)-enantiomer. With increasing ibuprofen dose, there was a less than proportional increase in the AUC of each enantiomer, while the AUCu for both enantiomers increased in direct proportion to the administered dose. The time-averaged unbound fraction of each enantiomer increased significantly with increasing dose, which caused the non-linearity between AUC and dose. It was predicted that the metabolic intrinsic clearance of each enantiomer, and the fraction of R(-)-ibuprofen which was metabolically inverted to S(+)-ibuprofen, was independent of the administered dose.
Adult↗
Rapid estimation of volume of distribution after a short intravenous infusion and its application to dosing adjustments.
A simple and a rapid method to estimate the apparent volume of distribution of drug after single or during multiple short-term intravenous infusion is proposed. This is based on the back extrapolation to the midpoint of infusion. An equation simpler than one previously reported in the literature is also derived to calculate the maintenance dose for multiple short-term intravenous infusion. In addition, an equation to estimate the "priming dose" for infusion during multiple infusion regimen is also derived. The derivations of the equations are based on a linear one-compartment open model for drug disposition in patients. The prposed method is thought to be adequate for the purpose of rapid individualization of dosage regimens. The simplicity of the method, in particular, the solution by the graphic method for estimation of the apparent volume of distribution, might be specially useful for clinicians not well versed in mathematics in applying clinical pharmacokinetics to drug therapy.
Humans↗
Bioequivalence requirements for generic products.
Many countries have established procedures for the introduction of generic pharmaceutical products. In order to protect consumers, these generic products must be demonstrated to be therapeutically equivalent to a previously approved product, typically an innovator product. The therapeutic equivalence of a generic and an innovator product is most commonly based on the demonstration of bioequivalence, i.e. clinically insignificant differences in the rate and extent of drug absorption usually assessed from pharmacokinetic measurements. This article reviews the bioequivalence requirements for generic products and, in the interest of promoting international harmonisation, highlights those areas where differences exist among countries.
Absorption↗
Effect of uranyl nitrate-induced renal failure on morphine disposition and antinociceptive response in rats.
1. The aims of the present study were to administer morphine (14.0 mumol/kg, s.c.) to male Hooded Wistar rats and to determine the effect of uranyl nitrate-induced renal failure on: (i) the antinociceptive effect of morphine; (ii) the pharmacokinetics of morphine and morphine-3-glucuronide (M3G); and (iii) the relationship between antinociceptive effect and the pharmacokinetics of morphine in plasma and brain. 2. Renal failure was induced by a single s.c. injection of uranyl nitrate and kinetic/dynamic studies were performed 10 days after its administration, when creatinine clearance was 17% of the control group. Antinociceptive effect was measured by the tail-flick method at various times up to 2 h post-drug administration. Concentrations of morphine and M3G in plasma and brain and concentrations of creatinine in urine and serum were determined by specific HPLC methods. 3. After morphine administration, the area under the antinociceptive effect-time curve was decreased by 44% in renal failure rats. There were no differences between control and renal failure rats in: (i) plasma morphine concentration-time curves; (ii) brain morphine concentration-time curves; and (iii) plasma M3G concentration-time curves. Morphine-6-glucuronide was not detected in any plasma or brain sample from rats administered morphine and no M3G was detected in brain. 4. For both control and renal failure rats, the relationships between antinociceptive effect and plasma morphine concentration were characterized by counterclockwise hysteresis loops, probably reflecting a delay for the relatively polar morphine to cross the blood-brain barrier. The relationship between antinociceptive effect and brain morphine concentration in control rats revealed no evidence of acute tolerance and was described by a sigmoidal function. In contrast, the relationship in renal failure rats was characterized by clockwise hysteresis, which is consistent with acute tolerance development.
Analgesics, Opioid↗
Effect of organic cations on the renal tubular secretion of pseudoephedrine in the rat.
1. Pseudoephedrine is a weak organic base that undergoes renal tubular secretion. The aim of the present study was to assess whether two other commonly used weak organic bases (cimetidine and morphine) inhibit the renal tubular secretion of pseudoephedrine in the rat isolated perfused kidney. 2. A total of 12 perfusions were performed with four perfusions in each of three treatment groups. In the control group, pseudoephedrine was administered as a bolus dose of [14C]-pseudoephedrine and unlabelled pseudoephedrine to achieve an initial perfusate concentration of 0.4 microg/mL. For the treatment groups, pseudoephedrine was administered as above and cimetidine or morphine was added to the perfusion medium in increasing concentrations of 0.5-12.5 and 0.2-5.0 microg/mL, respectively. 3. The mean (+/-SD) fraction unbound of pseudoephedrine alone in perfusate was 0.866+/-0.014 and was not different (P> 0.05) in the presence of cimetidine or morphine. 4. In control experiments, the renal excretory clearance (CLR) of pseudoephedrine was three-fold greater than glomerular filtration rate (GFR), yielding a ratio consistently greater than unity, which indicates extensive net tubular secretion of pseudoephedrine. The CLR and total clearance of pseudoephedrine were similar, suggesting an absence of renal metabolism of pseudoephedrine. 5. The CLR/GFR ratio for pseudoephedrine was not affected by morphine, but was significantly reduced (P < 0.05) in the presence of cimetidine. 6. The results indicate that cimetidine inhibits the renal tubular secretion of pseudoephedrine.
Adrenergic Agents↗
Glucuronidation of dihydrocodeine by human liver microsomes and the effect of inhibitors.
1. Glucuronidation is the major route of metabolism of dihydrocodeine (DHC) and accounts for 25-30% of an oral dose in urine. The kinetics of DHC-6-glucuronide formation in liver microsomes from five human donors and the effect of a number of potential inhibitor drugs were examined using a newly developed and validated HPLC assay. 2. The formation of DHC-6-glucuronide exhibited atypical kinetics that conformed to the Hill equation. The mean intrinsic dissociation constant (Ks) and maximum velocity (Vmax) values were 1566 micromol/L and 0.043 micromol/min per g, respectively. The Ks and Vmax values varied 1.5- and 3.5-fold, respectively. 3. Seven drugs were tested for inhibitory effects on DHC glucuronidation at low (50 micromol/L) and high (500 micromol/L) concentrations. At 50 micromol/L, only diclofenac produced greater than 50% inhibition, while at concentrations of 500 micromol/L inhibition was greater than 35% for diclofenac, amitriptyline, oxazepam, naproxen, chloramphenicol and probenecid, but not paracetamol. 4. The present study found little interindividual variation in the activity of human liver microsomes for glucuronidation of DHC. Comparison of the results from the inhibition studies with those reported previously for codeine and morphine suggest that the UDP-glucuronosyltransferase isoform UGT2B7 is involved in the glucuronidation of DHC.
Adult↗
Drug kinetics in childbirth.
Drugs from a wide range of pharmacological classes are commonly given to women in childbirth, either for a maternal effect or a fetal/neonatal effect. A number of striking physiological and biochemical changes occur during labour and delivery that might alter drug kinetics. The rate of drug absorption from the gastrointestinal tract may be normal in labour provided that narcotic analgesics are not administered concurrently. Altered blood flow characteristics in the extremities could modify drug absorption from intramuscular injection sites. Drug distribution might be altered as a result of the presence of placental-fetal tissues, or as a consequence of changes in, for example, maternal blood volume, concentrations of proteins and other endogenous compounds, cardiac output or tissue perfusion. Although data are scanty on the status of the physiological determinants of drug clearance, that limited information available suggests that drug clearance could be altered in childbirth. The possibility of a placental and/or fetal contribution should not be overlooked when considering the clearance of drugs administered during labour and delivery. Uterine contractions, maternal posture and obstetric medication have been found to affect the extent of some of the physiological changes that occur. Consequently, drug disposition could be modified by these factors. All of the drugs given to women in childbirth are capable of crossing the placenta to some degree. This is a disadvantage in those cases where drugs are given for a maternal effect and may result in neonatal sequelae. The fetal exposure to, and neonatal burden at delivery of, drugs administered during labour and delivery may be influenced by many factors, including maternal posture, mode of drug administration, the drug administraton to delivery interval, fetal pH, and whether intravenous bolus drug administration coincides with the contraction or relaxation phase of uterine activity. Protracted elimination by the neonate may occur for those drugs acquired in utero. Realisation of this is of considerable importance in the clinical management of the newborn.
Absorption↗
Renal tubular transport of morphine, morphine-6-glucuronide, and morphine-3-glucuronide in the isolated perfused rat kidney.
The isolated perfused rat kidney was used to examine the renal handling of morphine and its inactive metabolite morphine-3-glucuronide (M3G), and active metabolite morphine-6-glucuronide (M6G). The kidneys were perfused with Krebs-Henseleit buffer (pH 7.4) containing albumin, glucose, and amino acids, and drug concentrations were measured by high performance liquid chromatography. There was no conversion of morphine to the glucuronides or deconjugation of M3G or M6G. At an initial morphine concentration of 100 ng/ml, the unbound renal clearance to glomerular filtration rate ratio (CLur/GFR) was 5.5 +/- 3.2 (mean +/- SD), indicating that net tubular secretion of morphine occurred. In the presence of M3G (2000 ng/ml) and M6G (500 ng/ml) this Clur/GFR ratio was elevated to 17.3 +/- 4.8 (p less than .001), which implicates an interaction between these compounds at an active reabsorption transport system. The CLur/GFR ratio for M3G at 2000 ng/ml was 0.90 +/- 0.04, indicating the possibility of a small component of tubular reabsorption, and this ratio was not significantly altered in the presence of morphine and M6G. M6G was reabsorbed, probably actively, to a greater extent than M3G, with an initial CLur/GFR ratio of 0.67 +/- 0.04, which was not affected when morphine and M3G were coadministered. These data demonstrate an unusual phenomenon in that the glucuronide metabolites, which are larger and less lipophilic than the parent drug morphine, undergo net tubular reabsorption. The renal handling of morphine is a complex combination of glomerular filtration, active tubular secretion, and possibly active reabsorption.
Animals↗
Disposition of morphine and its 3- and 6-glucuronide metabolites during morphine infusion in the sheep.
A sheep preparation was used to examine the regional formation and extraction of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), relative to the regional extraction of morphine, at four morphine dose rates. On separate occasions, four ewes received a 15-min loading infusion of morphine sulfate, followed by a constant infusion at 2.5, 5, 10, or 20 mg/hr for an additional 5.75 hr. During the 5th to 6th hr of infusion, blood samples were collected simultaneously from the aorta, pulmonary artery, hepatic vein, hepatic portal and renal veins, posterior vena cava, and coronary and sagittal sinuses. Urine was collected for 48 hr. Morphine, M3G, and M6G in plasma and urine were determined simultaneously by HPLC. The blood/plasma concentration ratio (lambda) for morphine, M3G, and M6G was determined in spiked "blank" blood. Steady-state plasma concentrations were achieved during the sampling period, and dose-normalized concentrations were independent of the infusion rate. There was significant (p < 0.05) extraction (mean +/- SD) of morphine by the liver (0.676 +/- 0.014) and kidney (0.602 +/- 0.039), net extraction of M3G (0.106 +/- 0.046) and M6G (0.104 +/- 0.030) by the kidney, and net formation of M3G (-0.057 +/- 0.017) by the gut. The mean lambda for morphine, M3G, and M6G was 1.25 +/- 0.17, 0.80 +/- 0.03, and 0.82 +/- 0.09, respectively. The mean total body clearance of morphine with respect to blood was 1.58 +/- 0.27 liters/min. Mean (+/-SD) percentage urinary recoveries as morphine, M3G, and M6G were 14.7 +/- 8.5, 75.4 +/- 11.1, and 0.49 +/- 0.39, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗