Plasma concentration of α-methyldopa and sulphate conjugate after oral administration of methyldopa and intravenous administration of methyldopa and methyldopa hydrochloride ethyl ester

Summary The plasma concentrations of free -methyldopa and methyldopa sulphate conjugate were measured in 7 hypertensive patients with normal renal function following -methyldopa (1 g) orally. Five of these patients subsequently received -methyldopa ethyl ester (250 mg) (methyldopate) intravenously and two further patients received 250 mg of -methyldopa intravenously. After oral administration a large amount of total plasma -methyldopa was present as sulphate conjugate. There were wide interindividual differences in the ratio of free: conjugated -methyldopa in plasma (ratio at 4 hours ranged from 3.73 – 0.83) suggesting that individual differences in the extent of sulphate conjugation may occur. There was no close correlation between the degree of conjugation and the fall in arterial pressure. At all time intervals examined, plasma concentrations were higher following intravenous -methyldopa than -methyldopate. The plasma concentration of -methyldopa (free and esterified) 60 minutes after i.v. -methyldopate was 1.7±0.3 µg/ml wile at the same time after the same dose of methyldopa by the same route the mean concentration was 5.9 µg/ml. Although small amounts of sulphate conjugate were detected after i.v. -methyldopate, insignificant quantities of conjugate were found after i.v. -methyldopa. The average fall in mean arterial pressure was 27 mm Hg following i.v. -methyldopa but only 2.7 mm Hg following -methyldopate. These results suggest that sulphate conjugation of -methyldopa occurs in the gastrointestinal tract during absorption. Hydrolysis of -methyldopa ethyl ester does not appear to be instantaneous and pharmacokinetic differences between the ester and free -methyldopa have been demonstrated.     

Pharmacokinetics and pharmacodynamics of cicaprost in healthy volunteers after oral administration of 5 to 20 μG

Summary In a Phase I study, the tolerability, pharmacodynamics and pharmacokinetics of cicaprost have been investigated in 6 male volunteers given 5, 10, 15 and 20 g as tablets of the -cyclodextrin clathrate.Individual inhibition of platelet aggregation and changes in facial colour (measured by chromametry) were dose-dependent and reached a maximum 30 to 60 min post-dose. The maximum inhibition of platelet aggregation was about 40%. After 3 to 4 h pre-treatment values had returned. Blood pressure remained within the normal range. The peak plasma level of cicaprost was reached within 15 to 90 min after drug intake. Both C_max-and AUC were individually dose-dependent. The terminal half-life in plasma of cicaprost was approx. 1 h, and its total clearance amounted to 4–7 ml·min^–1·kg^–1. The time courses of the plasma levels and of the pharmacodynamic actions were in agreement. Interindividual differences were observed in the occurrence of unwanted effects (e.g. headache).Thus, cicaprost is an orally available PGI₂-mimetic, for which effects on platelet aggregation and vascular perfusion have been demonstrated in healthy volunteers after doses of 5 to 15 g.The results will form part of the M.D. thesis of T.Staks. Some of the findings were presented at the CPT meeting, Mannheim/Heidelberg, 1989     

Bioavailability and pharmacokinetics of isradipine after oral and intravenous administration: half-life shorter than expected?

Isradipine is a calcium channel-blocking agent of the dihydropyridine type, used in the treatment of hypertension. A terminal half-life of 8-9 hr has been reported, in several pharmacokinetic studies after oral administration of isradipine. In a yet unpublished study a much shorter half-life was observed, and the present trial was therefore conducted in order to estimate the half-life after intravenous administration of isradipine. The bioavailability was estimated as well. In a randomised cross-over design ten healthy young volunteers were given either isradipine orally or an intravenous infusion. The two study periods were separated by at least 3 days. Blood samples for measurement of isradipine concentration were collected for 10-12 hr after administration and half-life and bioavailability were estimated. Mean terminal half-life after intravenous administration was calculated to be 2.8 hr, and the bioavailability to be 0.28. None of the 10 subjects suffered from side effects. In the present intravenous study the half-life of isradipine seems to be of much shorter than demonstrated in previous oral studies.     

Pharmacokinetics and first-pass effects of ϵ-acetamidocaproic acid after administration of zinc acexamate in rats

1. Zinc acexamate (ZAC) is ionized to zinc and ?-acetamidocaproic acid (AACA). Thus, the pharmacokinetics and tissue distribution of zinc and AACA after intravenous (50?mg kg^?1) and oral (100?mg kg^?1) administration of ZAC were evaluated in rats. Also the pharmacokinetics of AACA after intravenous (10, 20, 30, and 50?mg kg^?1) and oral (20, 50, and 100?mg kg^?1) administration of ZAC and the first-pass extractions of AACA at a ZAC dose of 20?mg kg^?1 were evaluated in rats.

2. After oral administration of ZAC (20?mg kg^?1), approximately 0.408% of the oral dose was not absorbed, the F value was approximately 47.1%, and the hepatic and gastrointestinal (GI) first-pass extractions of AACA were approximately 8.50% and 46.4% of the oral dose, respectively. The incomplete F value of AACA was mainly due to the considerable GI first-pass extraction in rats.

3. Affinity of rat tissues to zinc and AACA was low—the tissue-to-plasma (T/P) ratios were less than unity. The equilibrium plasma-to-blood cells partition ratios of AACA were independent of initial blood ZAC concentrations of 1, 5, and 10?µg ml^?1—the mean values were 0.481, 0.490, and 0.499, respectively. The bound fractions of zinc and AACA to rat plasma were 96.6% and 39.0%, respectively.

     

Bioavailability and pharmacokinetics of β- methyldigoxin after multiple oral and intravenous doses

Summary To obtain true half lives, glycoside elimination from six healthy subjects was studied for 14 days after multiple intravenous doses or oral administration of a daily maintenance dose of -methyldigoxin 0.3 mg. After oral or intravenous administration of -methyldigoxin ceased, the plasma concentrations declined from the 14th to the 16th days with a half life of 1.7 days. From the 16th to the 20th day a change from a shorter to a longer half life of 2.8 and 2.9 days was observed. Similar half lives were found in urine: after the last dose the initial slope from the 14th to the 16th day had a half life of 1.8 days, and the terminal slope had one of 3.2 days. The results indicate release of the glycoside from slowly equilibrating tissues.Supported by the Deutsche Forschungsgemeinschaft     

Alterations in urinary 17α-Hydroxycorticosteroid excretion associated with administration of reserpine in the rhesus monkey

Summary Following single injections of reserpine in the Rhesus monkey, marked elevations of urinary 17-OH-CS excretion occurred, beginning 4 hours after administration of the drug, persisting about 8 to 10 hours, then levels subsided to return to normal by the next morning. The intensity and duration of the urinary 17-OH-CS response to reserpine are compared with the normal diurnal rhythm and with the response to the injection of standard doses of ACTH in the monkey. Repeated daily injection of reserpine for eight consecutive days produced a threefold urinary 17-OH-CS elevation the first three days followed by twofold elevations for the remaining five days. A marked increase in the percentage of free or unconjugated 17-hydroxycorticosteroids was also observed in these animals, suggesting possibly a concomitant renal or hepatic effect of reserpine administration.From thesis submitted by N. R. Rosenthal to the Department of Chemistry, Graduate School, Georgetown University, in partial fulfillment of the requirements for the degree of Doctor of Philosophy.     

Kinetic profile of N,N-dimethyltryptamine and β-carbolines in saliva and serum after oral administration of ayahuasca in a religious context

Ayahuasca is a beverage obtained from Banisteriopsis caapi plus Psychotria viridis. B. caapi contains the β-carbolines harmine, harmaline, and tetrahydroharmine that are monoamine oxidase inhibitors and P. viridis contains N,N-dimethyltryptamine (DMT) that is responsible for the visionary effects of the beverage. Ayahuasca use is becoming a global phenomenon, and the recreational use of DMT and similar alkaloids has also increased in recent years; such uncontrolled use can lead to severe intoxications. In this investigation, liquid chromatography–tandem mass spectrometry (LC–MS/MS) was used to study the kinetics of alkaloids over a 24 h period in saliva and serum of 14 volunteers who consumed ayahuasca twice a month in a religious context. We compared the area under the curve (AUC), maximum concentration (C_max), time to reach C_max (T_max), mean residence time (MRT), and half-life (t_1/2), as well as the serum/saliva ratios of these parameters. DMT and β-carboline concentrations (C_max) and AUC were higher in saliva than in serum and the MRT was 1.5–3.0 times higher in serum. A generalized estimation equations (GEEs) model suggested that serum concentrations could be predicted by saliva concentrations, despite large individual variability in the saliva and serum alkaloid concentrations. The possibility of using saliva as a biological matrix to detect DMT, β-carbolines, and their derivatives is very interesting because it allows fast noninvasive sample collection and could be useful for detecting similar alkaloids used recreationally that have considerable potential for intoxication.     

Plasma levels and β-blocking effect of α-hydroxymetoprolol—Metabolite of metoprolol—in the dog

The plasma levels and the - blocking effect of metoprolol and its active metabolite - hydroxymetoprolol have been studied after i.v. bolus injections of the substances to dogs. For both substances the - blockade increased with the dose, and there was a linear relationship between percent reduction in exercise heart rate and the logarithm of plasma concentration. The dose of the metabolite, however, had to be 5 times higher than that of metoprolol to induce the same degree of - blockade. Because of differences in the volume of distribution, 2.0 liters/kg for - OH-metoprolol and 3.5 liters/kg for metoprolol, the 5 times higher dose of - OH-metoprolol resulted in 10 times higher plasma levels of the metabolite than of metoprolol. - OH-Metoprolol was more slowly eliminated (t_1/27.0 hr, total body clearance 3.5 ml-kg^–1-min^–1) than metoprolol (t_1/22.0 hr, total body clearance 20.0 ml-kg^–1-min^–1). Approximately 5% of an i.v. dose of metoprolol was metabolized to - OH-metoprolol. The half-life of the endogenously formed metabolite was the same as after an i.v. dose of the compound.     

Trichloroethylene exposure in vapour degreasing and the urinary excretion of N-acetyl-β-d-glucosaminidase

In order to elucidate the potential nephrotoxicity of low level occupational exposure to trichloroethylene (TRI), urine analysis of the tubular enzyme N-acetyl--dglucosaminidase (U-NAG) was included in a cross-sectional study of metal degreasers in central Sweden. Eightysix percent of 8-h TRI in air measurements were well below 50 mg/m³. Normal levels of NAG were found in morning urine samples from 29 workers compared to a historical reference group. A weak positive correlation (r = 0.48;P <0.01) was observed between U-NAG activity and the concentration of the TRI metabolite trichloroacetic acid in urine but not with other estimates of recent or long-term exposure. In conclusion, TRI does not seem to be nephrotoxic at low exposure levels.     

Whole-body tissue distribution of total radioactivity in rats after oral administration of [¹⁴C]-bilastine

This study evaluated the tissue distribution of total radioactivity in male albino, male pigmented, and time-mated female albino rats after oral administration of a single dose of [1?C]-bilastine (20 mg/kg). Although only 1 animal was analyzed at each time point, there were apparent differences in bilastine distribution. Radioactivity was distributed to only a few tissues at low levels in male rats, whereas distribution was more extensive and at higher levels in female rats. This may be a simple sex-related difference. In each group and at each time point, concentrations of radioactivity were high in the liver and kidney, reflecting the role of these organs in the elimination process. In male albino rats, no radioactivity was measurable by 72 hours postdose. In male pigmented rats, only the eye and uveal tract had measurable levels of radioactivity at 24 hours. Measureable levels of radioactivity were retained in these tissues at the final sampling time point (336 hours postdose), indicating a degree of melanin-associated binding. In time-mated female rats, but not in albino or pigmented male rats, there was evidence of low-level passage of radioactivity across the placental barrier into fetal tissues as well as low-level transfer of radioactivity into the brain.     

Blood–brain barrier opening with alkylglycerols: Biodistribution of 1-O-pentylglycerol after intravenous and intracarotid administration in rats

Short-chain alkylglycerols have been described to increase the penetration of drugs and macromolecules across the blood–brain barrier (BBB) into the central nervous system (CNS) and were considered to be of potential value in the pharmaceutical treatment of CNS disorders. Due to the lack of information on the pharmacological behavior of these compounds in vivo, pharmacokinetics and biodistribution of [¹⁴C]- and [³H]-labeled 1-O-pentylglycerol (49 mg/kg, 100 mM) was investigated in normal male Wistar rats after intravenous as well as intracarotid administration. There was a rapid and predominant renal elimination of 1-O-pentylglycerol and more than 70% of administered dose was found in the urine within 270 min. Analysis of the pharmacokinetic parameters after a single i.v. bolus injection of 1-O-pentylglycerol resulted in a peak blood concentration of 0.58±0.06 μmol/ml, an initial half life of 23±7 min and a terminal half life of 18.8±4.1 h. No accumulation of 1-O-pentylglycerol was observed in the brain or other organs while highest concentrations were found in liver and thymus. This was confirmed by autoradiographic studies. Five minutes after intracarotid administration, high radioactivity was found in the ipsilateral brain, whereas after 30 min radioactivity in the brain has dramatically decreased. Autoradiographic images gave evidence of biliary excretion in addition to the renal elimination. There were no signs of cleavage of the O-alkyl bond in vivo as demonstrated by HPLC analysis.

In conclusion, 1-O-pentylglycerol is characterized by pharmacological properties appearing very favorable for in vivo use as a permeabilizing drug for increased drug delivery to the brain.     

Comparison of D₂ dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects

Quetiapine is an established drug for treatment of schizophrenia, bipolar disorder, and major depressive disorder. While initially manufactured as an immediate-release (IR) formulation, an extended-release (XR) formulation has recently been introduced. Pharmacokinetic studies show that quetiapine XR provides a lower peak and more stable plasma concentration than the IR formulation. This study investigated if the pharmacokinetic differences translate into different time curves for central D? dopamine receptor occupancy. Eleven control subjects were examined with positron emission tomography (PET) and the radioligand [11C]raclopride. Eight subjects underwent all of the scheduled PET measurements. After baseline examination, quetiapine XR was administered once-daily for 8 d titrated to 300 mg/d on days 5-8, followed by 300 mg/d quetiapine IR on days 9-12. PET measurements were repeated after the last doses of quetiapine XR and IR at predicted times of peak and trough plasma concentrations. Striatal D? receptor occupancy was calculated using the simplified reference tissue model. Peak D? receptor occupancy was significantly higher with quetiapine IR than XR in all subjects (50 ± 4% and 32 ± 11%, respectively), consistent with lower peak plasma concentrations for the XR formulation. Trough D? receptor occupancy was similarly low for both formulations (IR 7 ± 7%, XR 8 ± 6%). The lower peak receptor occupancy associated with quetiapine XR may explain observed pharmacodynamic differences between the formulations. Assuming that our findings in control subjects are valid for patients with schizophrenia, the study supports the view that quetiapine, like the prototype atypical antipsychotic clozapine, may show antipsychotic effect at lower D? receptor occupancy than typical antipsychotics.     

Metabolism of the plasticizer and phthalate substitute diisononyl-cyclohexane-1,2-dicarboxylate (DINCH®) in humans after single oral doses

Hexamoll^® DINCH^® (diisononyl-cyclohexane-1,2-dicarboxylate) is a new high-molecular-weight plasticizer and a phthalate substitute. In this study, the metabolism of DINCH^® was investigated by oral dosage of three male volunteers with approximately 50 mg Hexamoll^® DINCH^® (resulting in individual doses between 0.552 and 0.606 mg/kg body weight). Their urine samples were consecutively collected over 48 h. In analogy to di-iso-nonylphthalate (DINP) metabolism, we quantified the simple monoester mono-isononyl-cyclohexane-1,2-dicarboxylate (MINCH) and its secondary oxidized metabolites with HPLC–MS/MS via isotope dilution analysis. Additionally, we quantified the unspecific full breakdown product, cyclohexane-1,2-dicarboxylic acid (CHDA), via standard addition. All postulated metabolites were present in all samples analyzed. The unspecific CHDA was identified as the major urinary metabolite representing 23.7 % of the dose as the mean of the three volunteers (range 20.0–26.5 %). 14.8 % (11.3–16.7 %) of the dose was excreted as monoesters with oxidative modifications, in particular OH-MINCH 10.7 % (7.7–12.9 %), oxo-MINCH 2.0 % (1.5–2.6 %) and carboxy-MINCH 2.0 % (1.8–2.3 %). Less than 1 % was excreted as the simple monoester MINCH. In sum, 39.2 % (35.9–42.4 %) of the DINCH^® dose was excreted as these metabolites in urine within 48 h. Over 90 % of the metabolites investigated were excreted within 24 h after application. The secondary oxidized metabolites, with elimination half-times between 10 and 18 h, proved to be apt and specific biomarkers to determine DINCH^® exposure. With this study, we provide reliable urinary excretion factors to calculate DINCH^® intakes based on these metabolites in environmental and occupational studies.     

Increased urinary cadmium excretion and its relationship to urinary N-acetyl-β-d-glucosaminidase activity in smokers

To assess the renal effects of low-level exposure to cadmium due to smoking we examined blood and urinary levels of cadmium and urinary excretions of N-acetyl--d-glucosaminidase (NAG), ₂-microglobulin (BMG) and metallothionein in 94 male workers aged 18–55 years. Both blood and urinary cadmium levels indicated excess exposure to cadmium caused by smoking. The urinary cadmium concentration ranged between 0.1 and 5.0 g/g creatinine and increased significantly with age in the smokers. Neither urinary NAG nor BMG was increased in the smokers compared from non-smokers. A positive relationship between urinary cadmium and metallothionein was obtained not only in the smokers but also in the non-smokers. Furthermore, in the smokers urinary cadmium and metallothionein was positively related with urinary NAG. Since NAG in urine mostly originates from tubular cells by lysosomal exocytosis, the results may reflect an early cadmium effect on the lysosomal functions. Inhibitory effect of cadmium on the lysosomal degradation activities was discussed as a possible explanation of the positive relationship of urinary cadmium and metallothionein to urinary NAG.     

Plasma concentration — effect relationship of metoprolol during and after pregnancy

Summary The plasma drug concentration-effect relationship after an oral dose of 100 mg metoprolol has been studied in 8 women in the third trimester of a pregnancy complicated by hypertension. The study was repeated 3–5 months after parturition when all but 2 women were normotensive. Systolic and diastolic blood pressures (SBP and DBP) were measured in the sitting position followed by the change in heart rate on exercise. The average peak plasma concentration of metoprolol was almost 4-times higher in the non-pregnant state. Despite this difference, the reduction in exercise tachycardia and resting SBP was only slightly more pronounced after delivery than during pregnancy. In relation to the plasma drug concentration, metoprolol had four-times and twice the effect on heart rate and SBP during pregnancy as compared to the post partum period. The altered chronotropic response to metoprolol during pregnancy may be due to increased sensitivity or altered function of the -adrenergic system.     

Pharmacokinetics of risperidone in different application forms – Comparing long-acting injectable and oral formulations

We aimed to explore the differences in the pharmacokinetics of risperidone between oral and long-acting injectable (LAI) formulations using a large database of therapeutic drug monitoring (TDM). Plasma concentrations of risperidone (RIS), its active metabolite (9-OH-RIS) and the active moiety (AM) (RIS+9-OH-RIS), their concentration-to-dose (C/D) ratios and ratio of RIS/9-OH-RIS (an index of CYP2D6 metabolic activity) were used to compare patients receiving risperidone orally (n = 851) and those treated with LAI RIS (n = 63). Patients taking CYP inducers or inhibitors or with liver/renal impairment were eliminated. Our study demonstrated that patients on LAI RIS, despite slightly higher RIS doses in the oral group, showed no significant differences in total AM or 9-OH-RIS. Conversely, RIS concentration, RIS C/D ratio and total C/D ratio were slightly higher in the LAI RIS group, reaching significance due to the large sample size. More importantly, the median ratio of RIS/9-OH-RIS was 0.52 in LAI RIS vs. 0.25 in the oral group, providing a significant difference (p < 0.001). After controlling for confounding factors, we replicated the RIS/9-OH–RIS ratio increases in patients with LAI RIS, probably reflecting a decrease in first-pass metabolism. More studies are required to establish the clinical use of TDM for patients on LAI RIS.