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Biomedical subjects

D D Breimer

Publications and source records attributed to D D Breimer.

At least 127 records · Page 7Linked to original sources
PubMed1991

Grapefruit juice and cimetidine inhibit stereoselective metabolism of nitrendipine in humans.

The effects of grapefruit juice (150 ml at -15, -10, -1/4, +5, and +10 hours) and cimetidine (200 mg at the same times) on the stereoselective pharmacokinetics and effects of 20 mg oral racemic nitrendipine were investigated in a placebo-controlled crossover study in nine healthy men. In all subjects the AUC of racemic nitrendipine was increased by grapefruit juice (mean increase 106%; 95% confidence interval 64% to 158%) and cimetidine treatment (+154%; 95% confidence interval 77% to 265%). Comparable results were obtained for the peak plasma drug concentration and for both parameters of (S)- and (R)-nitrendipine. There were highly significant differences in the area under the concentration-time curve and peak plasma drug concentration between enantiomers within all treatments. Grapefruit juice had no effect on this stereoselectivity, but cimetidine increased the mean S/R ratio of areas under the curve (2.25) by 20% (95% confidence interval 12% to 29%) compared with placebo treatment (1.89). Half-lives and time to reach peak concentration of the enantiomers were not different within and between treatments. There were no consistent effects on blood pressure with all treatments, but in most subjects there was a small temporary increase in heart rate after intake of nitrendipine. Grapefruit juice and cimetidine did not affect these hemodynamic parameters and did not cause additional adverse effects.

Adult↗
PubMed1991

Differential effects of quinidine on the disposition of nifedipine, sparteine, and mephenytoin in humans.

The effects of quinidine on oxidative routes of drug metabolism mediated by different forms of cytochrome P450 were investigated in 10 healthy subjects. Each subject was studied on three different occasions and separately received oral administration of (1) a "cocktail" of nifedipine (5 mg), sparteine sulfate (90 mg), and mephenytoin (100 mg), (2) quinidine sulfate (200 mg), and (3) quinidine sulfate followed by the "cocktail" 1 hour later. Quinidine pretreatment significantly inhibited the aromatization of nifedipine to its major first-pass pyridine metabolite (M-0) and prolonged the elimination half-life of the calcium channel antagonist, both by about 40%. More marked inhibition of metabolism was observed with sparteine, and the formation of dehydrosparteine was abolished. A significant correlation was found between the 0-8-hour urinary ratio and the plasma concentration ratio of sparteine to dehydrosparteine obtained 4 hours after drug administration. No quinidine-induced changes were observed in the 4-hydroxylation of mephenytoin. The interaction between quinidine and nifedipine supports the involvement of a common P450 (P450IIIA4) in the metabolism of the two drugs.

Administration, Oral↗
PubMed1991

Lack of pharmacokinetic interaction between nifedipine, sparteine and phenytoin in man.

Nifedipine, sparteine and phenytoin were administered orally to eight healthy subjects separately and as a 'cocktail' on four different occasions to investigate any kinetic interactions. All subjects were extensive metabolizers of sparteine. After drug intake plasma and urine samples were collected up to 32 h and the concentrations of parent drugs and main metabolites were measured. Clearances and formation clearances were not significantly different after single substrate and 'cocktail' administration. Low or non significant correlation coefficients were found between the oxidation of the individual substrates or formation of their metabolites. With this strategy of simultaneous administration of substrates ('cocktail') it appears possible to characterize (and correlate) activities of different cytochrome P-450 isoenzymes, without the disturbing influence of intraindividual variation of drug oxidation with time.

Administration, Oral↗
PubMed1991

Stereoselective pharmacokinetics of oral and intravenous nitrendipine in healthy male subjects.

1. Stereoselectivity in the pharmacokinetics of nitrendipine was investigated by reanalysing plasma samples of a previously published study (Soons et al., 1989). 2. Racemic nitrendipine was administered intravenously (40 micrograms kg-1) and orally, both as plain tablet (20 mg) and in an osmotic pump device (40 mg Osmet) to nine healthy male subjects. Nitrendipine enantiomers were measured with a stereoselective assay. 3. Upon oral administration (tablet) the bioavailability of (S)-(-)-nitrendipine (13.4% +/- 5.6%) was 75% (50% - 98%) higher than that of (R)-nitrendipine (7.9% +/- 4.0%) (mean +/- s.d. (95% confidence interval)). Values of AUC and Cmax for (S)-nitrendipine were 90% (55% - 121%) and 77% (51% - 100%) higher respectively, than those for (R)-nitrendipine. Similar results were obtained with the osmotic system. 4. The clearance of intravenously administered (S)-nitrendipine was slightly (7%) lower than that of (R)-nitrendipine, but elimination half-lives and volumes of distribution were similar. 5. The difference in disposition of nitrendipine enantiomers is most likely related to a difference in activity of the cytochrome P-450 system towards the enantiomers, giving rise to a two-fold difference in first-pass elimination. 6. Stereoselectivity in the first pass metabolism of nitrendipine exhibited little intersubject variability and therefore is not a major factor in the wide variability in systemic availability of the more-potent (S)-enantiomer.

Administration, Oral↗
PubMed1991

The influence of Org 10172, a low molecular weight heparinoid, on antipyrine metabolism and the effect of enzyme induction on the response to Org 10172.

1. We have investigated the effect of repeated s.c. Org 10172 (a low molecular weight heparinoid; Lomoparan) treatment (1000 anti-Xa units twice daily for 5 days) on antipyrine (500 mg orally) metabolism, and the effect of enzyme induction by pentobarbitone (100 mg for 12 days) on the pharmacokinetics and pharmacodynamics of Org 10172 following an intravenous bolus injection of 3250 anti-Xa units. 2. Org 10172 treatment caused a small increase in the formation rates of all antipyrine metabolites (P less than 0.05), while the overall kinetics of antipyrine did not change significantly. 3. Oxidative enzyme induction by pentobarbitone, as demonstrated by an increased clearance of antipyrine, was associated with an increase in the area under the anti-thrombin activity vs time curve (P less than 0.05). No influence was seen on the kinetics of plasma anti-Xa and thrombin generation inhibiting (TGI) activity. 4. The pharmacodynamics of Org 10172, as determined by clotting tests, was not influenced by enzyme induction. 5. The clinical relevance of these observations is likely to be limited.

Administration, Oral↗
PubMed1991

Studies of interaction of a low-molecular-weight heparinoid (Org 10172) with cloxacillin and ticarcillin in healthy male volunteers.

Pharmacokinetic and pharmacodynamic interactions between Org 10172 (intravenous bolus injection of 3,250 anti-Xa units), which is a low-molecular-weight heparinoid, cloxacillin (500 mg orally four times daily for 3 days), and ticarcillin (4,000 mg intravenously four times daily for 2 days) were evaluated in two separate studies with healthy male volunteers (n = 18). Both cloxacillin and ticarcillin caused a significant increase in elimination half-life of anti-Xa activity, i.e., from 31 +/- 10 to 54 +/- 23 h and from 27 +/- 6 to 42 +/- 13 h, respectively (P less than 0.05). Ticarcillin decreased clearance (11%) and increased apparent volume of distribution (35%) (P less than 0.05), while for cloxacillin, these differences did not reach statistical significance. These changes in disposition of Org 10172 by the penicillins were not accompanied by important pharmacodynamic changes as evaluated by coagulation tests, platelet aggregation, and bleeding time. Cloxacillin appeared to influence blood coagulation (prolongation of the activated partial thromboplastin time and shortening of thrombin time; P less than 0.05) and facilitated thrombin-induced platelet aggregation, which coincided with a shorter bleeding time during the combined treatment in comparison with the time during treatment with Org 10172 alone (P less than 0.05). In conclusion, the disposition of Org 10172 was slightly changed by cloxacillin and ticarcillin, and, unexpectedly, cloxacillin appeared to have mild procoagulant effects.

Adolescent↗
PubMed1991

Pharmacokinetics of rectal drug administration, Part I. General considerations and clinical applications of centrally acting drugs.

Generally, oral administration is the route of choice in the daily practice of pharmacotherapy. However, in some circumstances this is impractical or even impossible (during nausea and vomiting or convulsions, in uncooperative patients and before surgery). In these cases, the rectal route may represent a practical alternative and rectal administration is now well accepted for delivering, for example, anticonvulsants, non-narcotic and narcotic analgesics, theophylline, antiemetics and antibacterial agents, and for inducing anaesthesia in children. It may also represent an interesting alternative to intravenous or other injection routes of drug administration. The rate and extent of rectal drug absorption are often lower than with oral absorption, possibly an inherent factor owing to the relatively small surface area available for drug uptake. In addition, the composition of the rectal formulation (solid vs liquid, nature of the suppository base) appears to be an important factor in the absorption process by determining the pattern of drug release. This relation between formulation and drug uptake has been clearly demonstrated for drugs like diazepam, paracetamol (acetaminophen), indomethacin, methadone and diflunisal. Coadministration of absorption-promoting agents (surfactants, sodium salicylate, enamines) represents another approach towards manipulating rectal drug absorption, although this concept requires further research concerning both efficacy and safety. For a number of drugs the extent of rectal absorption has been reported to exceed oral values, which may reflect partial avoidance of hepatic first-pass metabolism after rectal delivery. This phenomenon has been reported for morphine, metoclopramide, ergotamine, lidocaine (lignocaine) and propranolol. Rectal drug delivery in a site- and rate-controlled manner using osmotic pumps or hydrogel formulations may provide opportunities for manipulating systemic drug concentrations and drug effects. The extent of first-pass metabolism may be influenced (lidocaine), depending on the site of drug administration in the rectum. The rate of delivery may determine systemic drug action and side effects (nifedipine), and it may affect the local action of concurrently administered absorption promoters on drug uptake (cefoxitin). Local irritation is increasingly being acknowledged as a possible complication of rectal drug therapy. Long term medication with rectal ergotamine and acetylsalicylic acid, for example, may result in rectal ulceration, and irritation after a single administration of several drugs and formulations has been described. The assessment of tolerability and safety is imperative in the design of rectal formulations. Recent studies corroborate the clinical relevance of rectal drug therapy, and the value of the rectal route as an alternative to parenteral administration has been assessed for several drugs, e.g. diazepam, midazolam, morphine and diclofenac.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Rectal↗
PubMed1991

Pharmacokinetics of rectal drug administration, Part II. Clinical applications of peripherally acting drugs, and conclusions.

Part I of this article, which appeared in the previous issue of the Journal, covered general considerations, the physiology of the rectum, spreading of drugs into the colon, rectal absorption, partial avoidance of first-pass elimination, rate-controlled rectal delivery of drugs, irritation of the rectal mucosa and clinical applications of rectal administration, and discussed centrally acting drugs. In Part II, this discussion is extended to drugs which act peripherally and to methods of enhancing rectal drug absorption. The overall summary appeared in Part I.

Administration, Rectal↗
PubMed1991

Nonlinear first-pass metabolism of nifedipine in healthy subjects.

1. A dose-range study was carried out with nifedipine (NF) in 11 healthy subjects, who received orally 5, 10 and 20 mg in capsules (cap) and 20 mg as slow-release tablet. 2. The dose-normalized area under the curve (AUC) of NF showed significant nonlinearity: AUC of 5 mg (cap) was 312 +/- 179, of 10 mg (cap) 357 +/- 186 and of 20 mg (cap) 424 +/- 174 (ng.h/ml). The AUC of the tablet was significantly lower than that of 10 and 20 mg (cap), but not different from 5 mg (cap). 3. The dose-normalized AUC of the pyridine metabolite (M-0) significantly decreased with increasing dose: AUC of 5 mg (cap) was 244 +/- 88, of 10 mg (cap) 194 +/- 96 and of 20 mg (cap) 120 +/- 37 (ng.h/ml). 4. The excretion of M-I (which is ester-hydrolysed M-0) into urine was not different for any of the doses. 5. It is concluded that NF exhibits nonlinear first-pass metabolism, which concomitantly affects the formation of M-0, but not that of M-I.

Female↗
PubMed1991

Assessment of hepatic blood flow in healthy subjects by continuous infusion of indocyanine green.

1. The applicability of a continuous infusion of indocyanine green (ICG) to detect changes in apparent hepatic blood flow (HBF) was investigated in six healthy subjects. 2. High-performance liquid chromatography was used to measure ICG concentrations, and the effect of intravenous propranolol (10 mg in 10 min) on HBF was investigated. 3. During 150 min infusions of ICG (1.0 mg min-1) steady-state was reached within about 30 min and thereafter the plasma dye concentration remained essentially constant until the end of infusion. 4. Blood clearance (CLb) of ICG (15.9 +/- 2.2 ml min-1 kg-1; mean +/- s.d.), calculated as infusion rate/blood dye concentration over three time periods (30-50, 80-100 and 130-150 min) during the 150 min infusion, was not different from that obtained with three 1-min infusions (0.5 mg kg-1) administered at corresponding times of the day (CLb = 14.0 +/- 2.2 ml min-1 kg-1, P = 0.06). 5. The pharmacokinetics of ICG were shown to be linear up to plasma concentrations of at least 3 micrograms ml-1 using variable infusion rates (0.5, 1.0 and 2.0 mg min-1). 6. Propranolol had little effect on ICG concentrations during continuous infusion. The AUC of ICG from the start of propranolol infusion up to 125 min thereafter was increased by 12% +/- 17% (P = 0.21) compared with placebo.

Adult↗
PubMed1990

Enantioselective determination of felodipine and other chiral dihydropyridine calcium entry blockers in human plasma.

A sensitive method for the enantioselective determination of felodipine in human plasma is described. Following alkaline extraction with dichloromethane-pentane, racemic felodipine and its primary pyridine metabolite are simultaneously assayed using capillary gas chromatography on a DB-1 column, with electron-capture detection. The enantiomers of felodipine are quantitatively separated by high-performance liquid chromatography on a Chiralcel OJ column, containing tris(4-methylbenzoate)-modified cellulose coated on silica, and off-line detection using the same gas chromatographic system is applied. The limits of determination in plasma (and the inter-assay coefficient of variation (C.V.) at levels below 1 ng/ml) were 0.1 ng/ml (C.V. 13%) for felodipine, 0.1 ng/ml (C.V. 15%) for the enantiomers of felodipine and 0.3 ng/ml (C.V. 7%) for its pyridine metabolite. The method has proved to be applicable to several other chiral dihydropyridine calcium entry blockers, including nitrendipine, with comparable sensitivities.

Calcium Channel Blockers↗
PubMed1990

Effects of single-dose and short-term oral nifedipine on indocyanine green clearance as assessed by spectrophotometry and high performance liquid chromatography.

The effects of single-dose (10 mg) and short-term (10 mg tid) nifedipine treatment on apparent hepatic blood flow, as assessed by indocyanine green (ICG) clearance, were studied in ten healthy male subjects. ICG was measured by both spectrophotometric and high performance liquid chromatography (HPLC) assay methods. Blood clearance of ICG and apparent hepatic blood flow were increased by 30 and 50%, respectively, after single-dose nifedipine, whereas after 4 days' treatment these values were 12 and 30%. The spectrophotometric assay significantly overestimated ICG plasma concentrations from 7 minutes onwards. Although the spectrophotometric and HPLC assay showed marked differences in calculated half-lives and volume of distribution of ICG, the ICG clearance values were similar for the two assay methods.

Administration, Oral↗
PubMed1990

Topical effects of absorption enhancing agents on the rectal mucosa of rats in vivo.

In the present study, attempts have been made to assess the effects of cefoxitin formulations with various absorption promoters on mucosal integrity after rectal delivery in rats. Observations were made at 2 and 24 h following drug administration. On macroscopic and histologic evaluation, all drug formulations affected mucosal structure in terms of hyperemia, edema, loss of goblet cell vacuoles, detachment of enterocytes, and increase of the number of inflammatory cells; these effects were not reversible in 24 h. The effects of formulations with MGK (a mixture of glyceryl-1-monooctanoate, glyceryl-1,2-dioctanoate, glyceryl-1,3-dioctanoate, glyceryl trioctanoate, glycerol, and octanoic acid), monoglycerides, 3-amino-1-hydroxypropylidene-1,1-diphosphonate, and 4% (w/v) sodium tauro-24,25-dihydrofusidate (STDHF) tended to exceed those observed with sodium salicylate, medium-chain fatty acids, Azone, and lower STDHF concentrations. The clinically used suppository bases Witepsol H15 and PEG 1540/6000 and indomethacin suppositories also affected mucosal structure. Although the interanimal variability in scores was very substantial, results indicate that rectal absorption enhancement is associated with modification of paracellular transport after detachment of enterocytes. However, the extent of drug absorption enhancement appeared not to be directly related to the extent of mucosal damage.

Administration, Topical↗
PubMed1990

Absorption enhancement of rectally infused insulin by sodium tauro-24,25-dihydrofusidate (STDHF) in rats.

The bile salt derivative sodium tauro-24,25-dihydrofusidate (STDHF) has been reported to promote nasal absorption of insulin. In the present study the effect of STDHF on rectal insulin absorption was investigated in rats. At concentrations of 1 and 4% (w/v) it enhanced insulin bioavailability from 0.2 +/- 0.2 (control) to 4.2 +/- 3.2 and 6.7 +/- 2.1%, respectively, as assessed by radioimmunoassay. Insulin preparations with STDHF reduced blood glucose concentrations considerably in a concentration-dependent way. Coadministration of STDHF with Na2EDTA (0.25%, w/v) tended to increase further insulin bioavailability and hypoglycemic response. Varying the site of rectal administration did not influence these parameters.

Administration, Rectal↗
PubMed1990

Transport of desglycinamide-arginine vasopressin across the blood-brain barrier in rats as evaluated by the unit impulse response methodology.

The pharmacokinetic characteristics of desglycinamide-arginine vasopressin (DGAVP) with respect to its transport across the blood-brain barrier (BBB) were studied with the use of serial CSF sampling in an individual animal and the unit impulse response methodology. Transport rate is determined as BBB clearance, the volume of plasma per unit time cleared of the peptide by BBB transport, and the extent of transport as the percentage of the administered dose transported into the central nervous system. Plasma kinetics of DGAVP were shown to be linear within the dose range studied (50-150 micrograms), plasma mean residence time (MRT) being 18 +/- 4 min (mean +/- SE; n = 9). Elimination of DGAVP from CSF after icv administration was linear, with an MRT of 10 +/- 1 min (n = 9). After iv administration of 100 micrograms DGAVP, CSF concentrations were detectable for 90 min. Transport from plasma to the central nervous system was linear. The BBB transport clearance value was 1.0 +/- 0.3 microliters/min, and 0.026 +/- 0.007% of the administered dose was transported into the central nervous system. Results demonstrate that, within the concentration range studied, DGAVP is transported across the BBB by passive diffusion, although to a very low extent.

Animals↗
PubMed1990

The influence of infusion rate on the hemodynamic effects of felodipine.

The hemodynamic effects of the calcium entry blocker felodipine were studied during and after different infusion rates. Eight healthy normotensive volunteers had their individual pharmacokinetics of felodipine determined, and they subsequently entered a double-blind, randomized, crossover study. Individualized infusions of felodipine were given by a computerized infusion pump to reach plasma concentrations of 6 ng/ml (15.6 nmol/L) after 20 minutes, to be sustained for 8 hours (fast infusion) or the same plasma concentration after 8 hours (slow infusion). Control infusions with saline and vehicle were given. Blood pressure, heart rate, ECG conduction times, and baroreceptor sensitivity by the Valsalva test were measured, as well as the plasma concentrations of felodipine. The infusion system used produced the expected plasma concentration-time profiles with higher plasma concentrations after the fast infusion until 8 hours. Both slow and fast infusion increased heart rate (p less than 0.05) and produced a similar decrease in diastolic blood pressure (p less than 0.05). Slow infusion therefore reduced blood pressure more effectively. The tachycardia after the fast infusion was more pronounced during the first hour of the infusion but was indistinguishable from the slow infusion later, when plasma concentrations were still significantly different. Baroreceptor responsiveness was diminished by both felodipine treatments. There was no obvious difference in side effects caused by the two infusion regimes. The initial tachycardia after felodipine can be diminished by a slow rate of administration of the drug with a similar effect on blood pressure.

Adult↗
PubMed1990

Relationship between mephenytoin oxidation polymorphism and phenytoin, methylphenytoin and phenobarbitone hydroxylation assessed in a phenotyped panel of healthy subjects.

1. In a phenotyped panel of healthy subjects correlations were studied between the oxidation of mephenytoin, phenytoin, methylphenytoin and phenobarbitone, with respect to the formation of their 4-hydroxy metabolites (OH-). 2. On different occasions phenotyped extensive metabolizers (EM; n = 16) and poor metabolizers (PM; n = 4) of mephenytoin received phenytoin (100 mg), methylphenytoin (100 mg) and phenobarbitone (50 mg) and urine was collected up to 24 h. The excreted 4-hydroxy metabolites of all compounds were measured by h.p.l.c. 3. Urinary recovery of OH-phenytoin was 31.0 +/- 11.7%, of OH-methylphenytoin 3.4 +/- 2.7% and of OH-phenobarbitone 1.4 +/- 1.2%. No correlation was found between the recovery of OH-mephenytoin and OH-phenytoin. A subject who produced virtually no OH-phenytoin was an EM of mephenytoin, confirming a dissociation of mephenytoin polymorphism and phenytoin hydroxylation. 4. The correlation coefficient for OH-mephenytoin and OH-methylphenytoin recovery was 0.71 (Spearman rank, P = 0.002). The PMs of mephenytoin excreted the least amount of OH-methylphenytoin, suggesting a cosegregation of the 4-hydroxylation pathways. No correlation was found between the urinary recovery of OH-phenobarbitone and that of the other 4-hydroxy metabolites.

Adult↗