Biomedical subjects

D Brockmeier

Publications and source records attributed to D Brockmeier.

At least 19 recordsLinked to original sources

PubMed2006

Altruistic living donors: evaluation for nondirected kidney or liver donation.

A program was established within our regional procurement organization to permit evaluation of altruistic living donors (LD) interested in nondirected kidney or liver segment donation prior to transplant center referral. During the initial 30 months of program operations, 731 donor inquiries were received of which 131 individuals called back after review of mailed information materials. Forty-seven candidates initiated and 19 completed the evaluation process. Seven underwent donation to include six kidneys and one liver segment, five are actively pending donation, five were excluded from donation following transplant center evaluation and two took no further action after their intended liver recipients received deceased donor (DD) transplants. Psychological evaluation of these 19 candidates found them to be free of psychopathology, highly cooperative and self-directed. They did not exhibit attention-seeking or religious motivations for their actions. All seven donors and recipients continue to do well postoperatively. This evaluation program has made possible large-scale screening and education of prospective altruistic LD within the general population and also provides a unique opportunity to further our understanding of those individuals interested in living-nondirected donation.

Adult↗

PubMed2004

Investigation on interaction between tacrolimus and sildenafil in kidney-transplanted patients with erectile dysfunction.

OBJECTIVE: Sildenafil may provide an effective treatment for erectile dysfunction, frequently observed in uremic patients and after kidney transplantation. Pharmacokinetic interactions between sildenafil and tacrolimus are to be expected due to a common elimination pathway via cytochrome P450 3A4. Therefore, the pharmacokinetics during combined use of these agents were studied over 9 days. MATERIAL AND METHODS: Nine male patients (age 29-52 years) were included, who had previously participated in a recent interaction study with sildenafil given as a single dose. Comedication remained unchanged in order to avoid introducing confounding factors. In the previous study in the patients, tacrolimus blood levels with and without sildenafil were measured for pharmacokinetic analysis. In the present study, 25 mg sildenafil were coadministered daily over 9 days and tacrolimus levels were assessed at sampling times optimized using simulation. In addition, laboratory parameters and blood pressure changes were measured and adverse effects monitored. RESULTS: Terminal half-lives of tacrolimus did not differ significantly and trough levels did not change when sildenafil was coadministered daily over 9 days. Mean arterial blood pressure was lower after sildenafil intake. Two patients had to reduce their antihypertensive treatment, 6 patients reported mild side effects. In 1 case, there was an asymptomatic, temporary increase in the serum concentration of gamma-GT. CONCLUSIONS: There was no evidence obtained for a change in elimination half-life or average concentration of tacrolimus during repeated coadministration of sildenafil. Since blood pressure decreased, a starting dose of 25 mg sildenafil and, if necessary, adjustment of the dose of antihypertensive drugs on days when sildenafil is given has to be considered. With respect to the observed blood pressure changes, pharmacokinetic/pharmacodynamic interaction studies with other antihypertensive drugs are of critical importance in these patients.

Adult↗

PubMed2001

Interactions of sildenafil and tacrolimus in men with erectile dysfunction after kidney transplantation.

OBJECTIVES: To study the pharmacokinetics of the combined use of sildenafil (which may provide an effective treatment for patients with erectile dysfunction after kidney transplantation) and tacrolimus, as interactions between them are expected because of a common elimination pathway. METHODS: Ten male patients (age 29 to 52 years) were included. Because of its importance in transplant recipients, medication remained unchanged. On day 1, tacrolimus was administered routinely, and blood samples for tacrolimus assays were drawn at predefined times. On day 2, sildenafil was added and blood was collected for assays of tacrolimus, sildenafil, and the sildenafil metabolite UK103,320 (UK) at the indicated times. Blood pressure was monitored on both study days. Sildenafil and UK were assessed by high-pressure liquid chromatography and tacrolimus was assessed by microparticle enzyme immunoassay. RESULTS: No effects of sildenafil on the tacrolimus pharmacokinetics were found. However, in the patients studied, the sildenafil and UK pharmacokinetics were altered compared with the results of previous studies. The mean peak concentration of sildenafil was higher by 44% and the area under the concentration-time data increased by 90%. The elimination half-life was prolonged (4.7 hours compared with 3 hours in healthy volunteers). The area under the concentration-time data for UK was about threefold larger than in healthy volunteers, and the half-life was prolonged from 3.8 hours to 11.4 hours. Pronounced blood pressure drops were observed. CONCLUSIONS: Tacrolimus or the concomitant medication or the disease itself might have altered the sildenafil and UK pharmacokinetics. Because of the drop in blood pressure, sildenafil therapy should start at the lowest dose and any antihypertensive medication should be adjusted.

Adult↗

PubMed1999

Mean time concept and component analysis in pharmacokinetics.

In 1958, F.H. Dost [1958] defined the mean life-span ("mittlere Lebensdauer") of a total number of N molecules as the arithmetic mean of all times "z(i)" of any one of the N molecules residing in a pharmacokinetic system. This pharmacokinetic characteristic did not attract special interest for several years. Almost simultaneously Yamaoka et al. [1978], Cutler [1978], van Rossum [1978], Benet and Galeazzi [1979], and von Hattingberg and Brockmeier [1979] recommended the mean residence time (MRT) or mean time (MT) as a useful summarizing characteristic for complex pharmacokinetic systems. One of the most useful properties of the statistical analysis (also called "moment analysis" or "statistical moment analysis") of concentration-time data and in vitro dissolution profiles using moments is the additivity of mean times [von Hattingberg and Brockmeier 1978, 1979]. The very simple and compelling logic of additivity can be explained by the following example: considering an oral administration of a readily available dosage form, the distribution of each individual molecule within the body and the elimination from the body must be preceded by absorption of this molecule, which is trivial. However, as a consequence, the total transit time of an individual molecule through this system is the sum of its time up to absorption into the central circulation z(i).abs and the time the molecule spends in any part of the volume the molecule can reach z(i).vss. Therefore, the total mean time of all drug molecules available is the sum of the mean absorption time MT(abs) and the mean time in the steady-state volume of distribution MTvss. It is obvious that we can estimate the two components of the total mean time, i.e. MTabs and MTvss, by an appropriate experimental setting giving the drug once intravenously and determining MTvss and once giving the drug as an oral solution and deducing MTabs = MTtotal - MTvss. Because of this very useful property of the statistical analysis of concentration-time data by moments, this approach has been entitled "component analysis" [von Hattingberg et al. 1984].

Dosage Forms↗

PubMed1998

A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers.

OBJECTIVE: To analyse distributions of a urinary ratio of caffeine metabolites (MRc) representative of cytochrome P450 (CYP) 1A2 activity in a cohort of Caucasian German healthy volunteers and to re-assess the effects of smoking and oral contraceptives on the range and type of MRc distribution. METHODS: A cohort of volunteers comprising 192 individuals (96 males, 96 females) was divided into subgroups according to smoking and/or use of oral contraceptives. The CYP1A2 substrate caffeine was administered, and urine was collected for 6 h and analysed for representative caffeine metabolites. Distribution of a CYP1A2-dependent MRc was analysed using cumulative distribution (probit) plots and Rosin-Rammler-Sperling-Weibull (RRSW) functions. RESULTS: Cumulative distribution curves for males, and females, without further subgrouping for smoking habits and/or oral contraceptive steroid (OCS) consumption, showed slightly higher MRc values, i.e. slightly higher CYP1A2 activities, in males. Significantly higher MRc values were found in smokers of both sexes than in non-smokers. The distributions among female non-smokers or smokers with and without OCS were nearly super-imposible, however. For the two male subgroups, the sum of two RRSW functions resulted in a better adjustment to the data than a unimodal skewed distribution. A weak correlation between MRc and the number of cigarettes smoked per day was found. CONCLUSION: The inducing effect of smoking on CYP1A2 activity was confirmed, whereas no significant inhibitory effect of oral contraceptives was observed. The finding that the data are compatible with bimodal distributions in non-smokers suggests a significant impact of genetic factors on MRc. Among smokers, data were also compatible with bimodal distributions, i.e. with the existence of a "non-responder" phenotype concerning CYP1A2 induction by compounds present in tobacco smoke.

Adult↗

PubMed1995

Tight binding of ramiprilat to ACE: consequences for pharmacokinetic and pharmacodynamic measurements.

The pharmacokinetics of angiotensin converting enzyme (ACE) inhibitors are often difficult to characterize using standard tools. Most of the problems arise from the tight binding of ACE inhibitors to ACE. The present paper discusses how tight binding of ramiprilat to ACE affects the pharmacokinetic characteristics and in vitro measurement of ACE inhibition. Data from a randomized crossover study in healthy volunteers given 2 different dosage forms with 5 mg ramipril serve to compare the theoretically deduced predictions with actual measurements. The data confirm that elimination is concentration-dependent and that therefore the pharmacokinetics are non-linear. Renal clearance increases with concentration. With respect to pharmacodynamics, free ramiprilat depletion due to tight binding is the reason for the steep nature of concentration-effect curves often observed for ACE inhibition. This type of relationship, however, cannot be described by the classical Emax model nor by the sigmoid Emax model. The model of tight binding presented shows that the concentration-effect curve becomes steeper the larger the concentration of ACE and the greater the affinity of the inhibitor to the target molecule. With the classical Emax model the concentration can be doubled about 3 times to increase the measurable effect from 10 to 50% maximum effect, and because the relationship is symmetric at the EC50% point of inflection, the concentration can be doubled another 3 times to increase the effect from 50 to 90%. With the tight-binding concentration-effect relationship, doubling the concentration about 3 times may also increase the effect from 10 to 50% of the maximum effect, a further doubling of the dose, however, causes a steep increase of the effect from 50 to nearly 100%. This tight-binding concentration-effect relationship may also be present in other classes of drugs.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1994

Characterization of cyclosporine A uptake in human erythrocytes.

More than 70% of cyclosporine A (CsA) is bound to erythrocytes at whole blood concentrations of 50-1000 ng.ml-1. Cytosolic CsA is bound to the erythrocyte peptidyl-prolyl cis-trans isomerase cyclophilin. Measurements of serum CsA levels under clinical conditions are hampered by a temperature-dependent translocation of CsA into erythrocytes during cooling of the probes to room temperature. In order to characterize the kinetics of CsA uptake and to find a specific uptake inhibitor, we developed a method to measure the velocity of uptake based on rapid cooling of the erythrocyte suspension. The total erythrocyte-binding capacity for CsA amounted to 43 x 10(-5) nmol per 10(6) erythrocytes or 2.6 x 10(5) molecules per erythrocyte. Whereas the erythrocyte-binding capacity of CsA was temperature-independent between 10 degrees C and 42 degrees C, uptake kinetics of CsA were temperature-dependent. The Arrhenius plot for CsA uptake in human erythrocytes was linear and no transition temperature between 0 degree C and 42 degrees C could be detected. Therefore the CsA uptake process in human erythrocytes did not fulfil the criteria of carrier-mediated transport. This indicates that CsA diffuses passively into human erythrocytes. Hence, erythrocyte CsA uptake cannot be specifically inhibited.

Chromatography, High Pressure Liquid↗

PubMed1994

The influence of environmental and genetic factors on CYP2D6, CYP1A2 and UDP-glucuronosyltransferases in man using sparteine, caffeine, and paracetamol as probes.

The impact of gender, use of oral contraceptive steroids (OCS), coffee consumption and of smoking on the metabolism of sparteine, caffeine, and paracetamol was studied in 194 randomly selected subjects (98 male and 95 female). Thirty-eight of the male volunteers were cigarette smokers, 40 of the female subjects were smokers and/or users of OCS. The metabolic ratio of sparteine oxidation (MRs) showed a trimodal distribution. 7.7% of the subjects had a MRs > 20 and thus were poor metabolizers (PMs). Within the extensive metabolizer (EM) subjects, a distinct subgroup accounting for 11% was observed with 20 > MRs > 1.2. Six of the 15 phenotypical PMs were heterozygous EMs by genotyping. This indicates the existence of one or several CYP2D6 mutations which cannot be identified by the currently employed genotyping methods. In each subgroup, i.e. smokers/OCS and non-smokers/non-OCS, the cumulative frequency distribution of the heterozygous (wt/B) phenotype caused a shift to higher MRs compared with the wild-type homozygotes (wt/wt). Thus, for the in vivo activity of CYP2D6, genetic determinants prevail over environmental factors. Smoking, use of oral contraceptive steroids, caffeine consumption, or gender had no influence on sparteine metabolism. The distribution of the paracetamol glucuronide/paracetamol metabolic ratio appeared to be unimodal although skewed. Glucuronidation capacity was clearly affected by gender, OCS use and smoking. It was higher in male than in female subjects. Male smokers had the highest, and female non-smokers/non-OCS users the lowest metabolic ratio. CYP1A2 activity, as determined by a caffeine metabolic ratio ((AFMU + 1X + 1U)/1, 7U), was multimodally distributed and was clearly increased in smokers. It was significantly correlated to paracetamol glucoronidation in male heavy smokers (r=0.85), suggesting an element of co-regulation of CYP1A2 and of paracetamol conjugating UDP-glucuronosyltransferase isozymes, including UGTI.6.

Acetaminophen↗

PubMed1993

Substrate affinity of the protein tyrosine kinase pp60c-src is increased on thrombin stimulation of human platelets.

Human blood platelets contain high levels of non-receptor protein tyrosine kinases of the Src family, particularly pp60c-src, suggesting an important role for these enzymes in platelet physiology. Indeed, in response to various agonists of platelet function, a number of proteins become phosphorylated at tyrosine residues. However, no enzymic activation of an Src-related tyrosine kinase has yet been shown in platelets. In searching for the kinase(s) responsible, we found that all agonists tested that directly or indirectly activate protein kinase C in platelets (phorbol 12-myristate, 13-acetate, thrombin, vasopressin, collagen, calcium ionophore A23187) increased the overall activity of pp60c-src determined by IgG phosphorylation in an immunocomplex assay in the presence of low ATP concentrations. On the other hand, elevation of cyclic AMP directly by forskolin or indirectly by prostaglandin E1, or elevation of cyclic GMP by sodium nitroprusside did not significantly affect the activity of the enzyme. To substantiate the differences in enzyme activity, we determined Km and Vmax, values of pp60c-src from resting and thrombin-stimulated platelets. Thrombin treatment increased substrate affinity of pp60c-src as indicated by a 2- to 3-fold decrease in the Km values for ATP and the exogenous protein substrate casein. Vmax. values were only slightly altered under the assay conditions used. To further rule out modifications of pp60c-src in phosphorylation as a probable cause of the changed substrate affinity, we analysed tryptic phosphopeptides of immunoprecipitated, 32P-labelled pp60c-src of unstimulated and stimulated platelets. The platelet agonists listed above induced an increase in pp60c-src phosphorylation at Ser-12, which is the amino acid phosphorylated by protein kinase C. Surprisingly, we found that elevation of cyclic AMP did not affect 32P labelling of pp60c-src. On the basis of our data, we suggest that phosphorylation at Ser-12 might be one of the signal-triggering events that cause the increase in substrate affinity of pp60c-src.

Adenosine Triphosphate↗

PubMed1993

Multiple-dose pharmacokinetics of ramipril in patients with chronic congestive heart failure.

Thirteen patients with chronic congestive heart failure of NYHA class II-III received multiple doses (14 days) of ramipril (5 mg once daily); the concentrations of ramipril and ramiprilat in plasma, as well as ramipril, ramiprilat, glucuronides, diketopiperazine, and diketopiperazine acid in urine were measured at various times for 14 days. One patient dropped out after the first day due to hypotension and another who accidentally received another ACE inhibitor additionally was excluded, so that 11 patients completed the study. Ramipril and ramiprilat in plasma were determined by radioimmunoassay, and ramipril and its metabolites in urine were measured by gas chromatography in the laboratories of Hoechst AG. Peak concentrations of the active substance ramiprilat were reached after about 4 h and amounted to 22.3 +/- 11.1 ng/ml after the first dose, and a peak concentration of 26.6 +/- 10.0 ng/ml was observed 2.5 +/- 1.4 h on average after administration on day 14. Practically no accumulation was observed for ramiprilat; the AUD (0-24 h) values increased from 191.3 +/- 83.1 ng.h/ml for the first study day to 238.3 +/- 98.0 ng.h/ml for day 14. As expected, only very small fractions of the dose were excreted with urine as unchanged ramipril and ramipril glucuronide. Ramiprilat is excreted with urine to a larger extent than is rampiril--on average 6.6 +/- 3.0% on the first day and 12.2 +/- 3.8% on day 14. The total amount excreted increased by 34% on average, and was mainly due to an increased ramiprilat excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1992

Pharmacokinetic profile of cefodizime.

The pharmacokinetics of cefodizime (CDZ) were determined after i.v. and i.m. administration of single doses of up to 2 g and after i.v. administration of 2 g b.i.d. for six days. Serum concentrations were adequately described by three exponential functions, with a terminal half-life of about 4 h. Serum and urine levels and amounts excreted were dose-proportional, and derived pharmacokinetic characteristics were dose-independent. Steady state was established after the second dose (b.i.d.). CDZ is 100% bioavailable after i.m. administration. Concomitant administration of lidocaine did not alter either bioavailability or pharmacokinetic characteristics. Following administration of 1 and 2 g i.m., Cmax was reached after 1.2 h and amounted to 60 and 140 mg/l, respectively. CDZ is 88% bound to plasma proteins. CDZ was predominantly eliminated by the kidneys (80% of dose), a further 20% being excreted in the bile. Metabolites were not detectable in serum or urine. Dose adjustment does not seem warranted in the elderly. For renally impaired patients with CLcr between 30 and 10 ml/min, the daily dose should not exceed 2 g. For patients with CLcr below 10 ml/min, individual adjustment is suggested. CDZ showed good penetration into tissues and biological fluids (lung, bronchial secretions, pleural fluid, kidney, prostate, urine, bone, muscle, skin, Fallopian tube) with long-lasting concentrations. In urine, therapeutic concentrations were present for more than 24 h after administration of 1 and 2 g. Thus, on the basis of its pharmacokinetic profile, cefodizime is appropriate for effective treatment with once-daily administration.

Age Factors↗

PubMed1992

Pharmacokinetic profile of a novel slow release preparation of molsidomine.

A novel slow release preparation containing 24 mg molsidomine has been investigated in 6 healthy subjects. Individual concentration/time-profiles after the tablet showed two separate concentration peaks at 2.2 h and 15.0 h. The relative bioavailability of the slow release preparation in comparison to an aqueous solution of molsidomine was 0.67. The in vivo dissolution profile revealed either a progressive decrease in dissolution velocity caused by altered physico-chemical conditions in the ileum and the colon or a progressive reduction in the absorption constant. In all subjects deconvolution revealed a punctual increase in absorption about 15 h post-dose, coinciding with the second peak of the concentration/time-profile. Therapeutic plasma levels of molsidomine (greater than 5 ng.ml-1) were not maintained over 24 h by this slow release formulation.

Adult↗

PubMed1992

Influence of ramipril on plasma atrial natriuretic peptide, antidiuretic hormone, angiotensin II and aldosterone in patients with chronic congestive heart failure.

UNLABELLED: In an open trial 5 mg ramipril daily for 2 weeks was administered to 11 patients with congestive heart failure. 24-hour plasma profiles of atrial natriuretic peptide (ANP), antidiuretic hormone (ADH), angiotensin II (Ang II) and aldosterone (Aldo) were determined before and on days 1 and 15 of ramipril treatment, respectively. Urinary sodium excretion was also measured at the same time points. There were no relevant differences in the 24-hour profiles of ANP and ADH. Ang II values dropped as expected on the first day of ramipril treatment from 11.2 pg/ml to 2.9 pg/ml at 3 h post administration and from 6.7 pg/ml (predose) to 1.8 pg/ml at 2 h post administration on day 15. Plasma aldosterone values increased slightly from day 1 to day 15, sodium excretion increased from 125.9 mmol to 166.5 mmol/24 h; however, both changes in the 24-hour profiles were nonsignificant. A clinically relevant improvement in the severity of CHF was observed. From a total of 121 reported symptoms according to McKee et al., 35 showed an improvement; 81 remained unchanged, in only 5 symptoms a deterioration was observed. According to the NYHA-classification 5 patients improved from grade III to II, 6 remained unchanged. CONCLUSION: ACE inhibition does not induce changes in ANP or ADH levels in the resting state while Ang II decreases. A slight increase in aldosterone levels may be due to increased sodium excretion.

Aged↗

PubMed1991

Influence of ramipril on renal function in patients with chronic congestive heart failure.

Ramipril was administered to 13 patients, aged 49-80 years, weighing 53.5-90.3 kg, with congestive heart failure (CHF) for 2 weeks in an open trial. One patient dropped out after day 1 and another accidentally received another angiotensin-converting enzyme (ACE) inhibitor, so that 11 patients remained for analysis. Each patient received 5 mg of ramipril daily for 2 weeks, followed by a 1-week washout period. Urine was collected in 4-h fractions for 12 h followed by a 12-h fraction on days 1, 8, and 15. Creatinine clearance, as well as the excretion of albumin and the urinary brush border enzymes gamma-glutamyl transferase (GGT), alanine aminopeptidase (AAP), N-acetyl-beta-D-glucosaminidase (NAG), and lactate dehydrogenase (LDH) were determined. The values for albumin excretion, creatinine clearance, GGT, AAP, NAG, and LDH obtained for the various days during the time course before and during multiple dosing were subjected to an analysis of variance followed by Scheffe's test for means. Daily albumin excretion decreased during treatment with ramipril from 23.8 +/- 27.4 mg/24 h (baseline) to 12.9 +/- 15.1 (day 1), 10.8 +/- 15.6 (day 8), and 12.4 +/- 12.7 mg/24 h (day 15). The differences were significant (alpha = 0.05) when compared to pretreatment albumin excretion. Creatinine clearance increased from 78.8 +/- 38.3 ml/min (baseline) to 82.4 +/- 34.6 (day 1), 85.1 +/- 28.5 (day 8), and 91.7 +/- 36.4 ml/min (day 15). The change on day 15 was significant (alpha = 0.05) when compared to pretreatment values.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylglucosamine↗

PubMed1990

Evidence for muscarinic receptors in endothelial cells from combined functional and binding studies.

The aim of this study was to characterize muscarinic receptors of the bovine coronary artery by means of a combination of mechanical relaxation and contraction responses and radioligand binding data. Fresh helical strips of bovine coronary artery with intact endothelium relaxed in response to low concentrations (0.03-1 microM) of acetylcholine (ACh) and contracted at higher concentrations while endothelium-denuded strips only contracted. The ED50 for relaxation was 0.13 microM and that for contraction 1.8 microM (without endothelium); in the presence of endothelium, contraction dose-response curves were shifted to the right and the maximum contraction was reduced. In order to determine the location of the receptors mediating vasorelaxation, apparent affinity constants (KA) of ACh for relaxant and contractile effects were determined by irreversible blockade of a fraction of receptors with propyl benzilylcholine mustard (PBCM). The affinity constants (KA) were 0.22 microM for relaxation and 13 microM (with endothelium) and 20 microM (without endothelium) for contraction. In competition binding experiments against the muscarinic antagonist, [3H]N-methylscopolamine ([3H]NMS), the apparent affinity (KI) of ACh for binding sites in homogenates of endothelium-free coronary artery was 16 microM which was not different from the affinity constant determined in functional contraction experiments. Thus, the affinity constant of ACh determined for relaxation responses with endothelium-preserved vessels had no correlate in the binding affinity as determined with endothelium-free arteries. These findings indicate that bovine coronary arteries are relaxed by ACh through muscarinic receptors located on the endothelium whereas contractions are mediated by receptors on smooth muscle cells.

Acetylcholine↗

PubMed1990

Pharmacokinetics of prenylamine racemate and enantiomers in man.

Pharmacokinetics of racemic prenylamine were investigated in 6 healthy volunteers. Plasma levels were determined by gas chromatography/mass spectrometry. Concentration-time profiles were analyzed both by compartment-dependent and compartment-independent pharmacokinetic models. Terminal elimination half-life was 14.1 h (SD: 6.9 h). The apparent total clearance was 5.8 l/min. Mean residence time of racemic prenylamine was found to be 14.7 h (SD: 3.8 h). The relative bioavailability of prenylamine (Segontin 100) was 82.2% (SD: 9.9%) determined in six healthy volunteers. The volunteers received simultaneously the film tablet and 100 mg racemic dideuteroprenylamine as an aqueous solution of the lactate. This procedure is known to exclude intraindividual changes in absorption, first-pass metabolism or volume of distribution that might occur on sequential administration. The absolute bioavailability was estimated to be in the order of 15%. In a pilot study the pharmacokinetics of the enantiomers were investigated in 2 healthy volunteers. S-(+)-prenylamine was eliminated considerably faster from plasma than R-(-)-prenylamine suggesting a stereoselective metabolism. The AUC of the (+)-enantiomer was 20% of that of the R-(-)-prenylamine.

Adult↗

PubMed1989

Pharmacokinetic characteristics of roxatidine.

This article reviews the published and unpublished results of pharmacokinetic studies with roxatidine acetate in healthy volunteers of different ethnic origins, patients with various degrees of renal impairment, patients on maintenance hemodialysis, lactating women, and elderly patients. In addition, it reports on the findings of interaction studies with food and other drugs. The pharmacokinetic characteristics of roxatidine were found to be nearly identical for different doses, formulations, and ethnic groups. The decrease in relative total clearance (oral clearance) in patients with renal impairment and in the elderly can be explained almost completely by their level of renal function. As expected from the pharmacokinetic characteristics in healthy volunteers, only a small amount of roxatidine is removed by hemodialysis. Dose reduction is recommended in patients with renal impairment, but dose supplementation after hemodialysis is not necessary. Only a negligible fraction of the dose administered is excreted with breast milk. No pharmacokinetic interactions were found with theophylline, warfarin, propranolol, diazepam, and desmethyldiazepam, antipyrine or antacids. Food did not interfere with the absorption or disposition of roxatidine.

Aged↗

PubMed1988

Estimating reduced availability due to first pass elimination from relative total clearance and renal clearance.

A simple formula is presented for estimating the systemic availability of an orally administered drug from the relative total clearance (oral clearance) when renal clearance forms an important part of total clearance. Hepatic plasma flow is used in the equation and is represented by an average value taken from the literature. The formula is applied to data for cimetidine discussed in the literature. A further application is demonstrated for a drug under development for which an intravenous formulation was not available. It is possible to estimate the upper and lower limit of availability if some information on the amount of drug absorbed is available.

Administration, Oral↗