C. A. M. van Ginneken

Saturable Pharmacokinetics in the Renal Excretion of Drugs

SummaryThe renal excretion of drugs is the result of different mechanisms: glomerular filtration, passive back diffusion, tubular secretion and tubular reabsorption. Of these mechanisms the last 2 are saturable, as they involve carrier transport. This also implies that both tubular secretion and tubular reabsorption are susceptible to competition between similar substrates for a common carrier site. Furthermore, transport via these mechanisms is energy-dependent, so-called active transport, able to concentrate a drug.Tubular secretion takes place in the proximal tubule of the nephron. Many organic compounds are actively secreted, but there are separate carrier systems for anions and cations. Anions appear to be transported actively over the basolateral membrane and by a less efficient non-active carrier-mediated process (facilitated diffusion) over the brush border membrane. As a result of these mechanisms, anions tend to accumulate in proximal tubular cells. For cations, however, the active transport step operates over the brush border membrane, whereas the uptake of the cation in the cell occurs via facilitated diffusion over the basolateral membrane.Active reabsorption is most prominent for many nutrients and endogenous substrates (amino acids, glucose, vitamins), but various exogenous compounds also have a certain affinity for the reabsorptive carrier systems. Uricosuric drugs, for instance, interfere with carrier-mediated reabsorption of urate.The occurrence of saturable excretion routes causes dose-dependent, non-linear pharmacokinetics. In clinical pharmacokinetics, tubular secretion can adequately be described with the use of a Michaelis-Menten equation. This implies that a compound undergoing tubular secretion exhibits a concentration-dependent renal clearance. At low plasma concentrations the clearance will be maximal, and for several drugs may be as high as the effective renal plasma flow. Increasing concentrations cause decreasing renal clearance, until eventually the secretion mechanism becomes fully saturated. Then the excretion of the drug in urine will depend primarily on its net rate of filtration. It is important to realise that the non-linear kinetics will be evident from the plasma kinetics only when the saturable pathway contributes to at least some 20% of the total body clearance. Interactions with other substrates, however, are likely to occur even when only a very small amount of drug is transported by the carrier system. Non-linear kinetics inevitably lead to disproportionate accumulation. Therefore, for any drug that is actively secreted, careful consideration should be given to the possibilities of drug-drug interaction and of unwanted drug accumulation with increasing doses.

Identification of cannabivarins in hashish by a new method of combined gas chromatography-mass-spectrometry

Abstract The cannabis constituents cannabidiol, tetrahydrocannabinol and cannabinol in hashish are accompanied by the propyl analogues cannabidivarin, tetrahydrocannabivarin and cannabivarin. A new method was developed to identify these compounds by means of the combined gas chromatograph-mass spectrometer.

Gas chromatography of cannabis constituents and their synthetic derivatives

Abstract Twenty-five natural and forty-five synthetic cannabinoids have been identified by gas chromatography-mass spectrometry. It appeared that the retention times of groups of cannabinoids showed a characteristic pattern. An increase in the side-chain increases the retention time by a fixed amount of 42% per carbon atom. When the position of the side-chain is shifted from the ortho to the para position of the aromatic ring, the retention time is increased by a factor of 1.3. Reduction of the polarity by methylation and silylation reduces the retention time by a factor of 0.53. Branching of the side-chain results in an increase in the retention time by 12%. Saturation of the double bonds leads to a decrease in the retention time by a factor of 0.80.

Comparative plasma ampicillin levels and bioavailability of five parenteral ampicillin formulations in ruminant calves

Plasma ampicillin concentrations were determined in an eight-ways crossover trial involving six ruminant calves, which were treated intravenously (i.v.) with sodium ampicillin at 15.5 mg/kg and intramuscularly (i.m.) with five different ampicillin trihydrate or ampicillin anhydrate formulations at 7.7 mg/kg. The mean plasma concentration-time curve (Cp) after intravenous ampicillin sodium administration was described biexponentially, as: Cp = 38.8 e -0.0268t + 0.45 e -0.0058t. Intramuscular injection, into the lateral neck, of Ampikel-20 and Polyflex resulted in 100 per cent bioavailabilities within 12 h post injection (p.i.), but the biological half-lives (t1/2) were different, being 2.1 and 3.8 h, respectively. Ampikel-20 produced the highest peak plasma drug concentrations (mean C max :4.8 microgram ampicillin/ml). After intramuscular injection of Penbritin the mean bioavailability for the first 12 h p.i. was 63 per cent, the mean t1/2 was 5.9 h, and the mean Cmax was 1.8 microgram/ml. Treatment with Albipen and Duphacillin resulted in low plasma ampicillin levels, which were maintained for 3 to 6 days p.i., limited bioavailability during the first 12 h p.i., and a mean t1/2 of 22.2 and 11.9 h, respectively. Plasma concentrations of ampicillin from four hours onwards after i.m. and s.c. administration of Ampikel-20 at a dose level of 15.5 mg/kg were similar. The duration of potentially therapeutic plasma ampicillin concentrations after administration of each formulation is presented. Pre-slaughter withdrawal times for diseased calves are suggested for the different formulations studied.

Specimen handling and high-performance liquid chromatographic determination of furosemide

A simple high-performance liquid chromatographic method to measure furosemide in plasma and urine is described. Furosemide fluoresces best, but is unstable, at acidic pH and is subject to photochemical degradation. These factors were analysed and the results prompted changes in previously described methods. All specimens were very carefully protected from light; extraction and acidification were done with acetic acid instead of hydrochloric acid. With these precautions no 4-chloro-5-sulphamoylanthranilic acid was found in biological specimens. The main metabolite was furosemide glucuronide (20% of furosemide excretion). Sensitivity was 0.1 and 0.5 microgram/ml for plasma and urine, respectively. The applicability of our method for furosemide studies is demonstrated.

Linear and nonlinear kinetics of drug elimination I. Kinetics on the basis of a single capacity-limited pathway of elimination with or without simultaneous supply-limited elimination

The pharmacokinetic behavior of foreign substances that are completely or partially eliminated via metabolism by saturable enzyme systems is analyzed. General integrated equations are derived which describe the time course of the plasma concentration under the assumption of a saturable enzyme system according to Michaelis-Menten kinetics in combination with normal firstorder elimination processes. A procedure for the estimation of initial values of the elementary kinetic parameters on the basis of the models is outlined. These initial values have been used in a nonlinear curvefitting program in order to obtain reliable kinetic and enzyme parameters from the plasma curves. With these methods, kinetic and apparent enzyme parameters are calculated for ethanol, salicylic acid, 4-hydroxybutyric acid, and phenytoin.

A High-Performance Liquid Chromatographic Method for the Quantitative Determination of Naproxen and Des-Methyl-Naproxen in Biological Samples

Abstract A HPLC method for the quantitative analysis of naproxen and its major metabolite des-methyl-naproxen in biological fluid samples is described. Two methods of detection are compared: U.V. spectrophometry and spectrophotofluorometry. In both procedures an internal standard is used: diflunisal in the U.V. procedure and the ethoxy-analog of naproxen during fluorometry. The sensitivity of the fluorometric detection is higher than that of the U.V. detection; the limit being respectively 0.1 μg and 2.0 μg per milliliter sample. The fluorescence detection procedure can also be applied to very small samples (0.05 ml) in the therapeutic concentration rang range. Both procedures have been applied to clinical and laboratory studies in which they appear to be very satisfactory because of their ease of handling and their suitability for routinely performed analysis.

Pharmacokinetics of Biotransformation

Drugs and other chemical substances are eliminated from the human or animal body mainly by renal excretion and metabolic degradation in the liver. Substantial tubular reabsorption occurs, especially with lipophilic substances, so that the kidney’s part in the elimination of unchanged drugs can often be ignored.

Activation Energies of α-C-Oxidation and N-Oxidation of N-Alkyl-Substituted Amphetamines by Rat Liver Microsomes.: Stereochemistry and Deuterium Isotope Effects

Abstract1. The effects of temperature on the oxidative degradation of N-isopropyl-amphetamine by rat liver microsomes revealed a great difference in activation energy between the S(+) and R(-) isomers, indicating that different mechanisms are involved.2. Replacement of the α-H atoms of S(+)-isopropylamphetamine by deuterium caused a marked increase in activation energy (from 11.8 ± 0.9 to 18.6 ± 0.6 kcal/mol) and a decrease in the apparent value of Vmax. The deuterium effect indicates that breakage of the α-C-H bond is the rate-limiting step. No isotope effects were found on activation energy or Vmax with deuterated R(-)-N-isopropylamphetamine.3. For the N-dealkylation of N-isopropylphentermine and some N-dialkyl-substituted amphetamines, relatively high activation energies were found, comparable with that for the conversion of the laevo N-isopropylamphetamine (17.9–18.9 kcal/mol).4. These observations support the suggestion that in the dealkylation and deamination of the secondary amphetamines in the dex...

Age-dependent pharmacokinetics of phenylbutazone in calves.

The pharmacokinetics of phenylbutazone (PBZ) in relation to age was studied in calves. The drug was applied intravenously to calves (dose 22 mg/kg), which were divided, depending on age, into three groups. Heparinised blood samples were taken in defined intervals. The concentrations of phenylbutazone and two of its metabolites were determined in plasma by high performance liquid chromatography. The pharmacokinetic data derived from 1-month-old calves revealed a longer persistence (elimination half-lives twice as long, total body clearance 40-50% lower) of PBZ in the body than in the other two groups of calves aged 3-6 months. With respect to the long elimination half-lives (mean values 39-94 h), caution is needed in case of repeated doses (accumulation).