W. Krause

Pharmacokinetics of rolipram in the rhesus and cynomolgus monkeys, the rat and the rabbit. Studies on species differences

1. The pharmacokinetics of rolipram were studied in rat, rabbit, rhesus monkey and cynomolgus monkey using 14C- or 3H-labelled rolipram and a radioimmunoassay for measurement of unchanged drug. 2. Rolipram was rapidly and completely absorbed after oral doses of up to 50 mg/kg. Bioavailability was 0.1% in rhesus monkey, 3.7% in cynomolgus monkey, 3.6% in rabbit, 35% in rat, and 75% in man. 3. Rolipram was able to pass the blood-brain barrier achieving concentrations in brain twice those in plasma. 4. Plasma levels of the unchanged drug declined with a similar half-life of 1-3 h in all species investigated. In the rat, there were indications for a different clearance of the two rolipram enantiomers. 5. Labelled rolipram was excreted rapidly and completely. The main route of elimination was via the urine.

Pharmacokinetics of the Antidepressant Rolipram in Healthy Volunteers

1. The pharmacokinetics of rolipram were studied in healthy male volunteers using 3H-rolipram and a radioimmunoassay for measurement of unchanged drug. 2. Rolipram was rapidly and completely absorbed after an oral dose of 1 mg. Bioavailability was 73%. 3. Plasma levels of the unchanged drug declined with a terminal half-life of 2 h. The total clearance of rolipram was 2 ml/min per kg. 4. Labelled rolipram was excreted rapidly and completely. The main route of elimination was via the urine.

Dose proportionality of iopromide pharmacokinetics and tolerability after IV injection in healthy volunteers

Twelve healthy male volunteers participated in a single-blind, randomised, placebo-controlled cross-over study of IV iopromide in doses of 15 g iodine or 80 g iodine infused over a period of 15 min. The volunteers were observed for three days during which time blood samples, urine and faeces were collected.The terminal disposition phase half-life of iopromide was 2 h and 1.9 h, and the total clearance was 110 and 103 ml·min-1 at the lower and at the higher dose levels, respectively. The steady state volume of distribution was 16 and 17 l, indicating predominantly extracellular distribution of iopromide.Statistical analysis (one-sided t-test) showed that all the target parameters (AUC, half-life and urinary excretion) were equivalent at both dose levels, indicating dose proportionate, first order kinetics of iopromide over the large dose range tested. Iopromide was well tolerated after both doses.

The pharmacokinetics and biotransformation of14C-Lisuride hydrogen maleate in rhesus monkey and in man

Summary14C-labelled lisuride hydrogen maleate was administered intravenously (25 ug) and orally (200 ug) to three male and three female elderly volunteers. Following i.v. injection radioimmunologically determined plasma levels of unchanged lisuride showed a three-phasic decline with half-lives of 3 minutes, 16 minutes and 2.9 hours. The total clearance was 16 ± 9 ml/min/kg. Bioavailability was estimated to be 14% of oral dose.Determination of 1 4C-radioactivity did not show any specific enrichment of lisuride metabolites in cellular components of blood. The drug was almost totally metabolized and its degradation products were eliminated equally via the kidney and liver. Total recovery was about 90% of dose. The elimination half-life was 10 hours. Small parts of the dose administered were renally excreted with a halflife of 23 hours. Lisuride is metabolized extensively. HPLC radiochromatograms of freely extractable metabolites from urine did not show marked differences between both routes of administration. More than 15 compounds were freely extractable, only one of them represented more than 5% of dose. Phase II reactions were quantitatively unimportant.From rhesus monkey urine 6 metabolites were isolated. Chemical structures were proposed for 5 of them. They were assigned to the pattern of freely extractable human urinary metabolites and covered about 50% of radiolabel corresponding to about 13% of dose.The main freely extractable urinary metabolite was thought to be the 2-keto-3-hydroxy-lisuride derivative. Structures of the other four metabolites and earlier observations on the stability of the N′-ethyl-3H label led to the interpretation of independent changes of lisuride by different enzymatic processes such as oxidative N-deethylation, hydroxylation of the benzene system, monooxygenation at C2 and C9, and oxidation of double bonds atC2/C3 and C9/Ci0.

Pharmacokinetics of proterguride in rat and cynomolgus monkey

1. The pharmacokinetics of proterguride were studied in rat and cynomolgus monkey using 3H- and 14C-labelled drug and a radioimmunoassay for concentration measurements of unchanged drug. 2. Proterguride was rapidly and completely absorbed at low doses but not completely at higher dose levels, especially in rat. 3. Bioavailability was 18% in the monkey (low and high doses) and 79% (low doses) and 38% (high dose), respectively, in the rat. 4. Proterguride was able to pass the blood-brain barrier achieving concentrations in brain similar to those in plasma. 5. Excretion of labelled compounds was mainly in the faeces in rat, but in monkey elimination was equal in faeces and urine.

Pharmacokinetics of the dopamine partial agonist, terguride, in the rat and rhesus monkey

Summary3H-labelled terguride was rapidly and completely absorbed in the rat after oral administration of up to 50 mglkg. In the rhesus monkey, absorption was prolonged. The bioavailability of terguride was 79% in the rat and 15% in the monkey. Plasma levels of the unchanged drug declined with a half-life of 50 min (rat) or 20 min (monkey). Tissue distribution as studied by autoradiography in pregnant rats showed highest concentrations of labelled compounds in the liver, the cervical gland and the kidney. Lower levels were found in the thymus, the spinal cord, the placenta and the heart muscle followed by the fetal tissue, the muscles and the brain. Radioactivity was excreted mainly in the faeces when administered to the rat and to a higher extent in the urine after treatment of rhesus monkeys.

Pharmacokinetics and biotransformation of the anxiolytic abecarnil in healthy volunteers

1. The pharmacokinetics of abecarnil were studied in eight healthy male volunteers using 14C-abecarnil and an h.p.l.c. method for determination of unchanged drug. 2. Abecarnil was rapidly and nearly completely absorbed after an oral dose of 10 mg; bioavailability was 40%. Plasma levels of the unchanged drug declined with a terminal half-life of 4 h. The total clearance of abecarnil was 11 ml/min per kg. 14C-Abecarnil was excreted rapidly and completely. The main route of elimination was in the faeces. 3. Abecarnil was extensively metabolized resulting in ether cleavage at position 6 with subsequent glucuronidation or sulphation and, to a minor extent, in ester cleavage.

Pharmacokinetics of pirazolac — A new anti-inflammatory drug — in human volunteers I. Absorption, disposition, biotransformation and excretion

SummaryThe absorption, disposition, biotransformation and excretion of the nonsteroidal anti-inflammatory drug pirazolac were investigated in 6 volunteers (3 males, 3 females, age 50 > years) after intravenous and oral administration of 50 mg14C- p i r a z o l a c as an aqueous solution of the sodium salt.Pirazolac was very rapidly and completely absorbed and bioavailable when orally administered in a dose of 50 mg in solution. Maximum pirazolac levels in plasma of 6 μg/ml (≙30% of dose in total plasma volume) were already reached after approx. 20 minutes. No metabolites were detectable in the plasma. Pirazolac was eliminated from the plasma in two phases with half-lives of 3 hours and 16 hours, respectively, regardless of administration route.After intravenous and oral administration approximately 80% of t h e dose was excreted with the urine and approximately 15% with the feces within 7 days, indicating a complete excretion of l14C-radioactivity. In urine, approximately 10% of t h e dose was identified as unchanged pirazolac a n d 70% as pirazolac ester glucuronide.

Pharmacokinetics of Mepindolol Sulphate in Animals

SummaryPharmacokinetics of the new ß-receptor blocking agent mepindolol sulphate (CorindolanR) were investigated in rats and rabbits with special reference to effects which cannot be studied in man. Autoradiography after i.v. injection and distribution studies after oral dosing showed that in the rat these is no specific tissue accumulation of drug or metabolites either after single or multiple administration Mepindolol passes the blood-brain and placental barriers and achieves concentrations in the brain double those in the plasma, and in the liver of the foetus equal to that in the plasma of the mother. Renal excretion of mepindolol could be influenced by the urinary pH value. Acidic urine enhanced the elimination and basic urine retarded excretion of drug and metabolites.

Pharmacokinetics and metabolism of mespirenone, a new aldosterone antagonist, in rat and cynomolgus monkey

The pharmacokinetics and metabolism of mespirenone were examined in rat and cynomolgus monkey using the tritiated drug. Following i.v. administration, mespirenone exhibited a short half-life and a high plasma clearance; after oral administration the unchanged compound was not detectable. Thus, mespirenone has to be considered a pro-drug. From rat urine three metabolites were isolated by h.p.l.c. and identified by mass spectra and 1H n.m.r., all having retained the 7 alpha-sulphur substituent as a thiomethyl or a sulphinylmethyl group. The 7 alpha-thiomethyl metabolite had a half-life of six hours in rat plasma and its AUC value was 35% of that for total 3H. As this metabolite has marked anti-aldosterone activity, it is an active metabolite that contributes to the pharmacological effect of mespirenone.