Markku Anttila

Pharmacokinetic aspects of l-deprenyl (selegiline) and its metabolites

l‐Deprenyl (selegiline), an irreversible and selective inhibitor of monoamine oxidase type B (MAO‐B), is rapidly absorbed from the gastrointestinal tract and distributed into tissues. The reaction between MAO and selegiline takes place in two steps. The initial reversible reaction is followed by an irreversible reaction in which selegiline is bound covalently to the flavin part of the enzyme. Studies with positron emission tomography have shown retention of selegiline in brain areas with high MAO‐B activity, including striatal structures, hippocampus, thalamus, and substantia nigra. Inhibition of MAO‐B in vivo takes place rapidly; for example, platelet MAO is inhibited almost totally within the first 60 minutes after a single 10 mg oral dose of the drug. The recovery of MAO after inhibition depends on the organ and species in question. In rat brain the half‐life of recovery in the brain is approximately 8 to 12 days; in rat liver it is shorter, 1 to 3 days. Selegiline is metabolized into l‐(‐)‐desmethylselegiline, l‐(‐)‐methamphet‐amine, and l‐(‐)‐amphetamine mainly in the liver through the microsomal P‐450 system. The stereoselectivity of the metabolites is maintained; no racemic transformation takes place. All three main metabolites are found in human serum, cerebrospinal fluid, and urine, and l‐(‐)‐methamphetamine accounts for most of the metabolite pool. The metabolites are excreted mainly via urine. l‐(‐)‐Desmethylselegiline has been shown to be an irreversible inhibitor of MAO‐B in the rat and in humans.

Reversal of the sedative and sympatholytic effects of dexmedetomidine with a Specific α2-Adrenoceptor antagonist atipamezole: A pharmacodynamic and kinetic study in healthy volunteers

Background Specific and selective [Greek small letter alpha]2-adrenergic drugs are widely exploited in veterinary anesthesiology. Because [Greek small letter alpha]2-agonists are also being introduced to human practice, the authors studied reversal of a clinically relevant dexmedetomidine dose with atipamezole, an [Greek small letter alpha]2-antagonist, in healthy persons. Methods The study consisted of two parts. In an open dose-finding study (part 1), the intravenous dose of atipamezole to reverse the sedative effects of 2.5 [micro sign]g/kg of dexmedetomidine given intramuscularly was determined (n = 6). Part 2 was a placebo-controlled, double-blinded, randomized cross-over study in which three doses of atipamezole (15, 50, and 150 [micro sign]g/kg given intravenously in 2 min) or saline were administered 1 h after dexmedetomidine at 1-week intervals (n = 8). Subjective vigilance and anxiety, psychomotor performance, hemodynamics, and saliva secretion were determined, and plasma catecholamines and serum drug concentrations were measured for 7 h. Results The mean +/- SD atipamezole dose needed in part 1 was 104 +/- 44 [micro sign]g/kg. In part 2, dexmedetomidine induced clear impairments of vigilance and psychomotor performance that were dose dependently reversed by atipamezole (P < 0.001). Complete resolution of sedation was evident after the highest (150 [micro sign]g/kg) dose, and the degree of vigilance remained high for 7 h. Atipamezole dose dependently reversed the reductions in blood pressure (P < 0.001) and heart rate (P = 0.009). Changes in saliva secretion and plasma catecholamines were similarly biphasic (i.e., they decreased after dexmedetomidine followed by dose-dependent restoration after atipamezole). Plasma norepinephrine levels were, however, increased considerably after the 150 [micro sign]g/kg dose of atipamezole. The pharmacokinetics of atipamezole were linear, and elimination half-lives for both drugs were approximately 2 h. Atipamezole did not affect the disposition of dexmedetomidine. One person had symptomatic sinus arrest, and another had transient bradycardia approximately 3 h after receiving dexmedetomidine. Conclusions The sedative and sympatholytic effects of intramuscular dexmedetomidine were dose dependently antagonized by intravenous atipamezole. The applied infusion rate (75 [micro sign]g/kg-1 [middle dot] min-1) for the highest atipamezole dose was, however, too fast, as evident by transient sympathoactivation. Similar elimination half-lives of these two drugs are a clear advantage considering the possible clinical applications.

Pharmacokinetics and dissolution of two crystalline forms of carbamazepine

Abstract The dissolution, crystal growth in aqueous milieu and pharmacokinetics of carbamazepine, as the dihydrate and anhydrate, have been studied. The only difference in pharmacokinetics between the two forms was a somewhat higher absorption rate for the dihydrate. The slower absorption of the thermodynamically more active anhydrous form was attributed to rapid transformation, in aqueous milieu, of this form to the dihydrate, resulting in a fast growth in particle size.

Pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine.

The pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine—a novel α2‐adrenergic receptor agonist under development for preanesthetic use—were studied in healthy male volunteers. Single intramuscular doses of dexmedetomidine (0.5,1.0, and 1.5 µg/kg) and placebo were administered to six subjects in a single‐blind, multiple crossover study. Dexmedetomidine induced dose‐related impairment of vigilance assessed both objectively and subjectively. The drug also caused moderate decreases in blood pressure and heart rate. Plasma norepinephrine was dose‐dependently (maximum 89%) decreased. The intramuscular doses resulted in linearly dose‐related plasma concentrations of dexmedetomidine. Pharmacokinetic calculations revealed a time to maximum concentration from 1.6 to 1.7 hours, an elimination half‐life of 1.6 to 2.4 hours, an apparent total plasma clearance of 0.7 to 0.9 L/hr/kg, and apparent volume of distribution of 2.1 to 2.6 L/kg. The sedative effect of dexmedetomidine dissipated during the 6‐hour observation time, but all other effects were still evident 6 hours after administration of the higher doses, paralleling the plasma concentration curves. The relationship of plasma concentrations of dexmedetomidine to pharmacodynamic variables was consistent with a linear pharmacodynamic model. The pharmacodynamic‐pharmacokinetic profile of intramuscular dexmedetomidine may be suited to the proposed preanesthetic clinical use of this α2‐agonist.

Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin

Rifampin (INN, rifampicin) is a potent inducer of cytochrome P450 (CYP) enzymes involved in drug metabolism and therefore causes many drug interactions.

Picogram level determination of medetomidine in dog serum by capillary gas chromatography with negative ion chemical ionization mass spectrometry.

This paper describes a new gras chromatographic-mass spectrometric (GS-MS) assay for the determination of medetomidine in serum

Metabolism of toremifene in the rat

Toremifene was labelled to a specific activity of about 20 microCi/mmol with tritium at positions 3 and 5 in the para-substituted phenyl ring. At these positions tritium is not eliminated within the metabolic pathways. A mixture of unlabelled and labelled toremifene (5 or 10 mg/kg, 5 microCi/mg) was given i.v. or p.o. to Sprague-Dawley rats. The elimination of radioactivity was followed up by collecting urine and feces daily for 13 days. The elimination of toremifene which was similar after p.o. and i.v. administration took place mainly in the feces. About 70% of the total radioactivity was eliminated within 13 days, of this amount more than 90% in the feces. All applied radioactivity could be detected in three separate fractions according to the oxidative state of the side chain when counted by Berthold TLC Linear Analyzer. Each fraction was further separated into single metabolites by TLC or HPLC. Altogether 9 metabolites were identified and almost all methanol-extractable components were identified. The main metabolic pathways in the rat were 4-hydroxylation and N-demethylation. The side chain was further oxidized to alcohols and carboxylic acids. Small amounts of unchanged toremifene were found in the feces both after p.o. and i.v. administration indicating biliary secretion.

Pharmacokinetics of ftorafur after intravenous and oral administration

SummaryThe pharmacokinetics of ftorafur (FT), an antineoplastic agent, has been studied in seven cancer patients by determining concentrations of the unchanged compound in serum after single IV and PO doses of 2 g FT. Serum drug concentrations were determined by a new quantitative thin-layer chromatographic method. After IV administration, the mean half-lives of the distribution phase and elimination phase were 1.0 h and 7.6 h, respectively. Total serum clearance was 69 ml/h·kg and the apparent volume of distribution was 0.66 l/kg. Following PO administration there was a short lag-time, 11 min, before the appearance of FT in peripheral serum, and the maximum concentration in peripheral serum was achieved in 3.2 h. Oral absorption was complete and no significant first-pass metabolism could be observed. FT elimination, measured in serum taken from the portal vein and a peripheral vein, occurred substantially at the same rate after IV and PO administration. In contrast, after the PO dose FT appeared in the portal serum significantly earlier than in the peripheral serum, resulting in a difference of 1.7 h in the time of maximum serum concentration. This indicates fast gastrointestinal absorption of FT but hepatic retention (without metabolism) before the appearance of FT in the peripheral serum.

Pharmacokinetics of the novel antiestrogenic agent toremifene in subjects with altered liver and kidney function.

The pharmacokinetics of toremifene was investigated in an open study with four parallel groups of 10 subjects each. Subjects with impaired liver function (biopsy‐proven liver disease), activated liver function (drug‐induced), and impaired kidney function were compared with normal subjects.

Multiple-dose pharmacokinetics of selegiline and desmethylselegiline suggest saturable tissue binding.

The goal of this study was to examine the multiple-dose pharmacokinetics of selegiline and its metabolites desmethylselegiline, l-methamphetamine, and l-amphetamine after oral administration of selegiline HCl. Twelve healthy volunteers received 10 mg of selegiline HCl once daily for 8 days. The pharmacokinetic profiles of selegiline and the metabolites were examined from serum samples for 24 hours (i.e., the dosing interval, &tgr;) on days 1, 4, and 8. The results indicated significant apparent accumulation of selegiline and desmethylselegiline during the 8-day period of selegiline administration. The AUC&tgr;s of selegiline and desmethylselegiline were increased 2.7 fold (p < 0.001) and 1.5 fold (p < 0.001), respectively, from day 1 to day 8. However, the half-lives of selegiline (range, 1.5–3.5 h) and desmethylselegiline (range, 3.4–5.3 h) were found to be relatively short. Accordingly, the short half-lives of these compounds failed to predict the apparent accumulation. With both of the l-amphetamine metabolites of selegiline, steady state was reached by day 4. We suggest that the most likely explanation for the apparent accumulation of selegiline and desmethylselegiline was the saturation of the MAO-B binding sites in tissues, although decreased first-pass metabolism of selegiline cannot be ruled out. The observed increase in selegiline and desmethylselegiline concentrations on multiple dosing is not likely to significantly increase the pharmacodynamic effect or adverse effects of selegiline compared with what has been found after a single 10-mg dose.