Kalevi Pihlajamäki

Comparison of radioreceptor assay and radioimmunoassay for atropine: pharmacokinetic application

SummaryA membrane suspension prepared from rat brain was able to bind the potent muscarinic antagonist quinuclidinyl benzilate (QNB). The KD for binding was 0.48 nM and Bmax was 1.42 pmol/mg protein. Atropine competitively inhibited the binding of tritiated QNB to muscarinic receptors. This new radioreceptor assay (RRA) for atropine has been compared with a radioimmunoassay (RIA) for atropine. The RRA measures only the active component of atropine, 1-hyscyamine and in this respect it differs from the RIA. As little atropine as 1.25 ng/ml (4.33 nmol/l) in a 25 µl serum sample could be reliably assayed by the RRA. Using both assay techniques the pharmacokinetics of atropine was studied after a single 0.02 mg/kg i.v. dose given to 8 anaesthetized patients. The half-life calculated by the RRA was 3.7±2.3 h (m ± SD) and by the RIA 4.3±1.7 h. Both the volume of distribution and the total clearance were higher according to the RRA than the RIA: 3.9±1.5 vs 1.7±0.71/kg and 15.4±10.3 vs 5.9±3.6 ml/min/kg, respectively. The AUC measured by the RRA and RIA was 29.8±18.9 and 103.9±110.7 µg·h/l, respectively. The differences in the pharmacokinetics according to the 2 methods are presumably due to preferential tissue uptake of the l-form.

Effects of apomorphine on blood levels of homovanillic acid, growth hormone and prolactin in medicated schizophrenics and heatlhy control subjects

Two doses of apomorphine (0.005 mg/kg as a subcutaneous injection and 0.015 mg/kg as a 90 min i.v. infusion), and corresponding placebo treatments, were administered to 11 chronic medicated schizophrenic patients and to 8 healthy control subjects. The purpose of the study was to asses the usefulness of drug-induced alterations in the concentration of homovanillic acid (HVA) in plasma as indicators of dopamine autoreceptor sensitivity in the central nervous system. Growth hormone and prolactin in serum were also measured and used as indicators of postsynaptic dopaminergic drug effects. In the control subjects, i.v. apomorphine increased growth hormone in serum from 1.8 +/- 0.2 to 28.3 +/- 4.6 ng/ml and reduced prolactin by 57 +/- 7%. In the patients, apomorphine caused only weak neuroendocrine effects. HVA in plasma was not affected by apomorphine in either group of subjects. The results for growth hormone and prolactin indicate that postsynaptic dopamine receptors in the tubero-infundibular system are antagonized to a considerable degree also during chronic treatment with neuroleptics. The lack of effect of apomorphine on HVA levels suggests that HVA in plasma is not a sensitive indicator of the inhibition of dopamine release caused by small doses of apomorphine and mediated through dopamine auto-receptors. Supersensitivity of this class of receptors could not be demonstrated in our patients, which contrasts with some earlier results.

Disposition of nomifensine after acute and prolonged dosing

The pharmacokinetics of nomifensine were studied after single oral and intravenous doses. The effect of prolonged oral dosing on the pharmacokinetics of nomifensine was also evaluated. Nomifensine was rapidly absorbed from the gastrointestinal tract. The peak concentration of free nomifensine (0.18 μmol/L) was reached at 1.13 hours after dosing. The highest concentration after the intravenous dose was 1.21 μmol/L. The elimination t½after a single dose was about 4 hours regardless of the route of administration. Nomifensine was extensively distributed in body fluids and tissues, with an apparent volume of distribution of 8.69 L/kg. The AUC of free nomifensine after oral dosing was only 26.5% of that after intravenous infusion. Absorption from the gastrointestinal tract was complete, and the AUCs of total nomifensine were equal after all treatments. The main reason for limited bioavailability seems to be extensive first‐pass metabolism during the absorption process. The AUC of free nomifensine decreased substantially (from 0.78 to 0.32 hr · µmol/L) and the elimination t½was shortened (from 4.39 to 2.11 hours) after a 2‐week dosing period. These effects suggest marked induction of the metabolizing enzymes. An increase in nomifensine dosage may be needed in some patients to maintain a full therapeutic effect.

Inotropic Action and Myocardial Uptake of Digoxin and Betamethyldigoxin in Isolated Guinea Pig Atria

The chronotropic and inotropic effects as well as the tissue levels of digoxin and methyldigoxin were studied in isolated guinea pig atria. Higher concentrations of methyldigoxin than of digoxin were required to cause arrhythmias. The inotropic potencies of the two glycosides did not differ from each another in equimolar concentrations in the organ bath. The increase in contractility correlated with the level of the glycoside in the organ bath and in the tissue. Digoxin was more effectively taken up by the heart tissue than methyldigoxin. Thus, when the tissue levels of the glycosides were the same, the contractility was greater after methyldigoxin than after digoxin.