Some physico-chemical properties of amphetamine and related drugs.
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Amphetamine↗
Biomedical subjects
T B Vree
Publications and source records attributed to T B Vree.
Pharmacokinetics, acetylation-deacetylation, renal clearance, and protein binding of sulphamerazine, N4-acetylsulphamerazine, and N4-trideuteroacetylsulphamerazine in 'fast' and 'slow' acetylators.
Sulphamerazine shows a clear acetylator phenotype. The half-life of elimination of sulphamerazine is 12 h in 'fast' and 24 h in 'slow' acetylators. N4-Acetylsulphamerazine is eliminated biphasically, characterized by half-lives of 5 and 12 h in 'fast' and 5 and 24 h in 'slow' acetylators. Protein binding of sulphamerazine (86 per cent) and N4-acetylsulphamerazine (92 per cent) is independent of acetylator phenotype or the origin of the compound, whether it is present in the body as parent compound or metabolite. The renal clearance of sulphamerazine (20 ml min-1) and N4-acetylsulphamerazine (300-500) ml min-1) is independent of the acetylator type and the origin of the compound. The existence of an acetylation-deacetylation equilibrium in the metabolism of sulphamerazine has been demonstrated with the test drug N4-trideuteroacetylsulphamerazine, which inhibits the renal excretion and clearance of N4-acetylsulphamerazine.
Acetylation↗
Pharmacokinetics, metabolism and renal excretion of sulfatroxazole and its 5-hydroxy- and N4-acetyl-metabolites in man.
Hydroxylation is the predominant pathway of metabolism for sulfatroxazole in the body, accounting for 70 per cent of the dose. Fifteen per cent of the dose is acetylated unimodally and 10 per cent is excreted unchanged. The half-lives of sulfatroxazole and its metabolites 5-hydroxysulfatroxazole and N4-acetylsulfatroxazole are approximately 22 h after administration of sulfatroxazole. N4-acetylsulfatroxazole, taken as parent drug, is eliminated by renal excretion (92 per cent of the dose). The initial elimination half-life of N4-acetylsulfatroxazole is 4.5 h, which later increases to 70 h as the result of the acetylation-deacetylation equilibrium. Probenecid inhibits the renal excretion of the metabolites 5-hydroxy- and N4-acetylsulfatroxazole. Inhibition of the N4-acetyl metabolite favours the deacetylation, which results in an increase of the T 1/2 of sulfatroxazole from 20 to 30 h. The protein binding value of sulfatroxazole is 84 per cent, that of N4-acetylsulfatroxazole is 37 per cent. Sulfatroxazole is excreted renally by passive processes, while the metabolites are excreted by both passive and active processes.
Acetylation↗
Comparative bioavailability and kinetics of folinic acid in the pharmaceutical formulations of Rescuvolin and Ledervorin in healthy volunteers.
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Administration, Oral↗
Pharmacokinetics of diazepam and four 3-hydroxy-benzodiazepines in the cat.
Biotransformation and elimination of diazepam and four 3-hydroxy-benzodiazepines after i.v. injection in anaesthetized cats were investigated. Decay of plasma concentration of 3-hydroxy-benzodiazepines was slow and plasma concentrations of their glucuronides were lower than of unchanged parent compounds. In the urine, very low excretion rates of all investigated benzodiazepines were found during the first eight hours. It is concluded that cats poorly glucuronidate 3-dydroxy-benzodiazepines.
Animals↗
High performance liquid chromatography and preliminary pharmacokinetics of rufloxacin and its metabolites N-desmethylrufloxacin and rufloxacinsulfoxide in plasma and urine of humans.
An HPLC analysis was developed for the measurement of rufloxacin and two of its possible metabolites N-desmethylrufloxacin and rufloxacinsulfoxide. Humans are unable to form these two metabolites, while no other metabolites could be detected in the HPLC chromatogram. The half-life of elimination of rufloxacin in two human subjects was 27 and 38 h respectively, while a constant percentage of 25-26% of the dose is excreted unchanged in the urine.
Adult↗
Intravenous regional anesthesia with 0.5% articaine, 0.5% lidocaine, or 0.5% prilocaine. A double-blind randomized clinical study.
BACKGROUND AND OBJECTIVES: The purpose of this study was to compare the effectiveness of three local anesthetic agents for intravenous regional anesthesia in the upper limb. Side effects and plasma concentrations of the drugs in the doses administered for IVRA were also studied. METHODS: Thirty patients in ASA groups I and II received intravenous regional anesthesia for surgery of the upper limb. In a double-blind prospective study, they were randomly allocated to receive one of three local anesthetics: articaine, lidocaine, or prilocaine. Patients received 40 mL of a 0.5% solution of the local anesthetic. The onset time of sensory block was assessed by pinprick and the extent of motor block was was scored as 0-3. Plasma concentrations of local anesthetics were determined in all patients from serial arterial blood samples drawn at predetermined times before and after tourniquet release. RESULTS: The onset time of sensory block was significantly shorter (2.5 minutes) in the articaine group than in the lidocaine group (11.1 minutes) or the prilocaine group (10.9 minutes) (Scheffe, P < .05). Development of motor block was equal in all three groups (score 2). Estimation of plasma concentrations by high performance liquid chromatography showed that the peak level in all 30 patients was reached immediately after release of the tourniquet; plasma concentrations thereafter gradually declined. Maximum concentrations of articaine, lidocaine, and prilocaine were, 1.85, 8.5, and 4.4 micrograms/mL, respectively. No signs of local anesthetic toxicity of the cardiovascular or central nervous systems were seen. CONCLUSION: Articaine had the fastest onset of sensory block and the lowest peak plasma concentration of the three local anesthetics when used for intravenous regional anesthesia.
Adult↗
Pharmacokinetics of sulphamethoxazole in man: effects of urinary pH and urine flow on metabolism and renal excretion of sulphamethoxazole and its metabolite N4-acetylsulphamethoxazole.
A high performance liquid chromatography method for the determination of sulphamethoxazole and its metabolite N4-acetylsulphamethoxazole is described. The renal excretion rate and cumulative renal excretion of sulphamethoxazole is markedly influenced by urinary pH. With constant urinary pH, the renal excretion rate and the renal clearance of sulphamethoxazole is dependent on the urine flow. The renal clearance of the metabolite N4-acetylsulphamethoxazole is not influenced by urinary pH or urine flow. No clear acetylator phenotype could be detected in the group of volunteers studied. The extent of acetylation depends on the amount of sulphamethoxazole available for acetylation, thus indirectly on the urine pH and flow.
Absorption↗
Pharmacokinetics of N1-acetyl- and N4-acetylsulphamethoxazole in man.
The pharmacokinetics of N1-acetylsulphamethoxazole and N4-acetylsulphamethoxazole in man are described. N1-Acetylsulphamethoxazole is deacetylated to sulphamethoxazole and acetylated to N4-acetylsulphamethoxazole. N4-Acetylsulphamethoxazole is excreted almost unchanged in the urine. The renal excretion rate is independent of the urine flow and urinary pH. N4-Acetylsulphonamides are less lipid soluble and more acidic than their corresponding parent sulphonamides.
Acetylation↗
Determination of the acetylator phenotype and pharmacokinetics of some sulphonamides in man.
The pharmacokinetics of sulphamethizole, sulphamethoxazole, sulphadiazine, sulphapyridine and sulphadimidine have been studied in man. Renal clearance values of the metabolite N4-acetylsulphonamide are 6 to 20 times higher than those of the corresponding parent compound. The renal clearance of sulphonamides is dependent on the urine flow. N4-Acetylsulphonamide concentration-time profiles for plasma and urine have been constructed for the sulphonamides. The percentage N4-acetylsulphonamide-time profiles for plasma are excellent tools for establishing the acetylator phenotype, while those constructed from urine samples are less useful. Evidence is obtained that sulphadimidine is metabolically processes by 2 different isoenzymes, while sulphadiazine, sulphapyridine and sulphamethoxazole are processes by 1 acetylating isoenzyme. Sulphamethizole is acetylated to very little extent.
Acetylation↗
Deuterium isotope effects and stereochemistry in the dealkylation and deamination of amphetamines and ephedrines in man.
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Amphetamine↗
Codeine analgesia is due to codeine-6-glucuronide, not morphine.
Eighty per cent of codeine is conjugated with glucuronic acid to codeine-6-glucuronide. Only 5% of the dose is O-demethylated to morphine, which in turn is immediately glucuronidated at the 3- and 6-position and excreted renally. Based on the structural requirement of the opiate molecule for interaction with the mu-receptor to result in analgesia, codeine-6-glucuronide in analogy to morphine-6-glucuronide must be the active constituent of codeine. Poor metabolisers of codeine, those who lack the CYP450 2D6 isoenzyme for the O-demethylation to morphine, experience analgesia from codeine-6-glucuronide. Analgesia of codeine does not depend on the formation of morphine and the metaboliser phenotype.
Analgesics, Opioid↗
Pharmacokinetics, N1-glucuronidation, and N4-acetylation of sulfa-6-monomethoxine in humans.
Sulfamonomethoxine (S) is metabolized by O-dealkylation, N4-acetylation, and N1-glucuronidation. In humans, only N1-glucuronidation (12%) and N4-acetylation (36%) takes place. The N1-glucuronide is directly measured by HPLC. When N4-acetylsulfamonomethoxine (N4) is administered as the parent drug, N1-glucuronidation does not occur. After an oral dose, fast and slow acetylators show a similar t1/2 for S (25.0 +/- 4.6 hr vs. 29.8 +/- 4.8 hr; p = 0.459), and the t1/2 of the N4-acetyl conjugate is also similar in fast and slow acetylators (25.0 +/- 4.64 hr vs. 29.8 +/- 4.8 hr, p = 0.459). The intrinsic mean residence time of N4 is 7.1 +/- 2.3 hr. The mean total body clearance of S is 5.0 +/- 1.3 ml/min, the renal clearance is 0.84 +/- 0.26 ml/min, and the volume of distribution at steady state is 11.7 +/- 3.4 liters. The renal clearance of N4 is 17.89 +/- 4.19 ml/min. No measurable concentrations of the N1-glucuronide of S are found in plasma. The protein binding of S is 92%. N1-glucuronidation results in an 80% reduction in the protein binding of S (11%). N4 shows a high protein binding of 98%. Approximately 60% of the oral dose of S is excreted in the urine.
Acetylation↗
Ciprofloxacin does not impair the elimination of diazepam in humans.
The pharmacokinetics of a single iv dose of 10 mg diazepam and the renal excretion of its metabolites resulting from N-demethylation and C-3-hydroxylation were investigated in 10 healthy volunteers when diazepam was administered alone and on day 3 of administration of the fluoroquinolone ciprofloxacin (500 mg twice per day). No significant changes in the diazepam half-life, its volume of distribution, the total body clearance, or the renal clearance were observed. In addition, the renal excretion of the metabolites desmethyldiazepam, 3-hydroxydiazepam (temazepam), and 3-hydroxydesmethyldiazepam (oxazepam) were not altered by ciprofloxacin co-medication. These data demonstrate that in a 500 mg twice per day oral dosage, ciprofloxacin does not influence the metabolic clearance of diazepam in young healthy volunteers.
Adult↗
Plasma concentrations after high doses of mepivacaine with epinephrine in the combined psoas compartment/sciatic nerve block.
A combination of psoas compartment block and sciatic nerve block was performed with a total dose of 731.5 mg mepivacaine (55 ml, 1.33%) with epinephrine (1:600,000) in patients scheduled for orthopedic surgery on one leg. In 20 patients, arterial blood samples were collected at timed intervals over a 6-hour period to determine the mepivacaine plasma concentration. In all patients, good sensory and motor blocks were obtained and no analgesics were required during surgery. Despite the high dose of mepivacaine, the plasma concentrations stayed below 6.0 micrograms/ml, with one exception, although no clinical signs of local anesthetic toxicity were observed. Plasma pharmacokinetic variables of mepivacaine were as follows: Cmax: 4.22 mg.l-1 (SD, 1.28); Tmax: 0.99 hours (SD, 0.76); T1/2: 3.25 hours (SD, 1.12); CL 0.55 1.hour-1.kg-1.
Adult↗
Preclinical pharmacokinetics of the antitumor antibiotic deshydroxy-sparsomycin in beagle dogs.
Sparsomycin (Sm) is a well known inhibitor of protein synthesis with anticancer potential. In order to minimize toxicity of this drug and increase its activity, several analogues were synthesized. Deshydroxy-Sm (dSm) appeared to be a good candidate for further investigations because of its lower toxicity and significantly higher antitumor activity in several ascitic tumors in mice. Pharmacokinetic evaluation in beagle dogs was performed using either single iv bolus or continuous infusion administrations. The drug was eliminated with a terminal t1/2 beta of 0.8 +/- 0.08 hours (48 +/- 5 minutes). The mean volume of distribution was 0.4 +/- 0.06 l.kg-1. The mean total body clearance was 6.4 +/- 0.8 ml.min-1.kg-1. The drug is eliminated mainly by the kidneys (54%). Active tubular secretion and active tubular reabsorption of the drug were observed. The pharmacokinetics was linear until the lethal dose. The results of this study provided additional data useful in selection of potentially useful analogues for further preclinical studies.
Animals↗
Bupivacaine toxicity secondary to continuous cervical epidural infusion. Case report.
BACKGROUND AND OBJECTIVES: A case is described of bupivacaine toxicity after continuous cervical epidural infusion in a patient with intractable cancer pain. The patient had several periods of generalized tonic clonic seizures. Serial venous blood samples were taken after the first signs of toxicity. The highest total plasma bupivacaine level was 20.3 micrograms/mL. The corresponding free bupivacaine concentration was not determined. The highest measured free bupivacaine concentration was 1.21 micrograms/mL, corresponding with a total plasma bupivacaine level of 6.7 micrograms/mL. There were no signs of cardiovascular toxicity. The patient recovered after treatment without adverse sequelae. METHODS: A plasma concentration-time curve was constructed. There was a rise in the plasma concentration of bupivacaine after the continuous infusion was stopped. RESULTS: Total body clearance of bupivacaine was 20 mL/min and elimination half-life was 27 hours. CONCLUSIONS: The case emphasizes the importance of serial plasma concentrations of bupivacaine after continuous epidural infusion and the value of free bupivacaine concentration versus total bupivacaine concentration.
Analgesia, Epidural↗