Showing papers in "British Journal of Clinical Pharmacology in 1986"
TL;DR: The results clearly indicate that the bronchial hyperreactivity to airway spasmogens observed in asthma is exclusively an in vivo phenomenon not involving increasing sensitivity of bronchia smooth muscle.
Abstract: Responses of human bronchial strip preparations to contractile and relaxant agonists were measured in preparations from non-diseased and from asthmatic lung obtained 3-15 h post-mortem. The potencies of carbachol and histamine were approximately two times less in asthmatic than in non-diseased bronchi. This was statistically significant for carbachol (P less than 0.05), but not for histamine (P greater than 0.05). These results clearly indicate that the bronchial hyperreactivity to airway spasmogens observed in asthma is exclusively an in vivo phenomenon not involving increasing sensitivity of bronchial smooth muscle. The potencies of the beta-adrenoceptor agonists isoprenaline, fenoterol and terbutaline were significantly reduced by 4-5 fold in asthmatic bronchi compared with non-diseased airways. In contrast, theophylline was equipotent in the two populations of airway preparations. Thus, it appears that severe asthma is associated with decreased bronchial smooth muscle beta 2-adrenoceptor function.
255 citations
TL;DR: There is growing evidence that the observed interaction is caused not by the parent drugs, but by the 4-oxo metabolite of enoxacin, pefloxac in and ciprofloxACin and nalidixic acid.
Abstract: Enoxacin decreases the metabolic clearance of the bronchodilator theophylline not only in severely ill patients, but also in patients with stable chronic obstructive airways disease. In this comparative study, significantly increased plasma theophylline concentrations were measured during co-administration of enoxacin (110.9%) and, to a lesser degree, also during co-administration of pefloxacin (19.6%) and ciprofloxacin (22.8%). Total body clearance of theophylline was significantly decreased by enoxacin (63.6%), ciprofloxacin (30.4%) and pefloxacin (29.4%). The pharmacokinetic parameters of theophylline did not change during co-administration of ofloxacin and nalidixic acid. There is growing evidence that the observed interaction is caused not by the parent drugs, but by the 4-oxo metabolite of enoxacin, pefloxacin and ciprofloxacin.
240 citations
TL;DR: Repeated oral administration of amlodipine to 28 volunteers resulted in steady state plasma drug concentration being reached after seven doses, an accumulation of approximately threefold and a mean half-life of 45 h.
Abstract: Intravenous administration of amlodipine (single dose, 10 mg) to 12 volunteers gave a mean plasma half-life of 34 h, mean clearance of 7 ml min-1 kg-1 and a mean apparent volume of distribution of 21 l kg-1. Oral administration (single dose, 10 mg) to the same 12 volunteers gave a mean systemic availability of 64% and a mean plasma half-life of 36 h. In a second study, repeated oral administration (once daily for 14 days, 15 mg) to 28 volunteers resulted in steady state plasma drug concentration being reached after seven doses, an accumulation of approximately threefold and a mean half-life of 45 h.
219 citations
TL;DR: The pharmacokinetics of sal butamol and its sulphate conjugate metabolite were investigated after intravenous and steady-state oral administration of salbutamol to 10 healthy volunteers, finding the drug eliminated on the first-pass could be accounted for entirely as sulphates formed, presumably, in the intestinal wall.
Abstract: The pharmacokinetics of salbutamol and its sulphate conjugate metabolite were investigated after intravenous and steady-state oral administration of salbutamol to 10 healthy volunteers. With intravenous administration, total plasma clearance was 480 +/- 123 ml min-1, elimination half-life was 3.86 +/- 0.83 h and apparent volume of distribution was 156 +/- 381. Urinary excretion of unchanged drug and sulphate conjugate were 64.2 +/- 7.1% and 12.0 +/- 3.1% of the dose, respectively. With oral administration, systemic availability was 0.50 +/- 0.04, and urinary excretion of unchanged drug and sulphate conjugate were 31.8 +/- 1.9% and 48.2 +/- 7.3% of the dose, respectively. The drug eliminated on the first-pass could be accounted for entirely as sulphate conjugate formed, presumably, in the intestinal wall. Renal clearance of salbutamol was 291 +/- 70 ml min-1 after intravenous and 272 +/- 38 ml min-1 after oral administration, while the renal clearance of the sulphate conjugate was 98.5 +/- 23.5 ml min-1 after oral administration. Heart rate increased with increasing plasma salbutamol concentration, although a lag was evident. The effect on heart rate was lower after 24 h continuous oral salbutamol administration.
188 citations
TL;DR: The plasma protein binding of basic drugs appears to vary more than was at first assumed and is related to the marked intra-and interindividual differences in one of the chief binding proteins, AAG.
Abstract: The plasma protein binding of basic drugs appears to vary more than was at first assumed and is related to the marked intra-and interindividual differences in one of the chief binding proteins, AAG. Changes in AAG concentrations will result in alterations in the distribution and metabolism of basic drugs which will complicate the interpretation of the relationship between total drug concentration and drug efficacy or toxicity. For some drugs, e.g. lignocaine, direct measurement of free concentrations may improve their clinical use but rapid and reliable techniques are as yet not readily available.
167 citations
TL;DR: The pharmacokinetics of caffeine (CA), paraxanthine (PX), theobromine (TB) and theophylline (TP) were studied in six healthy male volunteers after oral administration of each compound on separate occasions.
Abstract: The pharmacokinetics of caffeine (CA), paraxanthine (PX), theobromine (TB) and theophylline (TP) were studied in six healthy male volunteers after oral administration of each compound on separate occasions. The total plasma clearances of CA and PX were similar in value (2.07 and 2.20 ml min-1 kg-1, respectively) as were those for TP and TB (0.93 and 1.20 ml min-1 kg-1, respectively). The unbound plasma clearances of CA and PX were also similar in magnitude (3.11 and 4.14 ml min-1 kg-1, respectively) as were those of TP and TB (1.61 and 1.39 ml min-1 kg-1, respectively). The half-lives of TP and TB (6.2 and 7.2 h, respectively) were significantly longer than those of CA and PX (4.1 and 3.1 h, respectively). The volume of distribution at steady state of TP (0.44 l kg-1) was lower than that of the other methylxanthines (0.63-0.72 l kg-1). The unbound volume of distribution of TP (0.77 l kg-1) was however the same as that of TB (0.79 l kg-1) whereas the unbound volume of distribution of PX (1.18 l kg-1) was similar to that of CA (1.06 l kg-1).
153 citations
TL;DR: In two patients taking dipyridamole the mean dose of adenosine which produced an electrophysiologic effect (restoration of sinus rhythm or ventricular slowing to under 100 beats min-1) was 1.0 +/- 0.52 mg, whereas in other patients themean dose was 8.8 +/- 2.6 mg, suggesting potentiation of the action ofadenosine by dipyrIDamole.
Abstract: Increasing doses of adenosine were given by rapid intravenous bolus to seven patients with spontaneous supraventricular tachycardia. Adenosine restored sinus rhythm in 10 of 14 episodes of narrow complex tachycardia. In those patients in whom adenosine produced only transient ventricular slowing the underlying rhythm was atrial flutter. Transient dyspnoea occurred in all patients. In two patients taking dipyridamole the mean dose of adenosine which produced an electrophysiologic effect (restoration of sinus rhythm or ventricular slowing to under 100 beats min-1) was 1.0 +/- 0.52 mg, whereas in other patients the mean dose was 8.8 +/- 2.6 mg, suggesting potentiation of the action of adenosine by dipyridamole.
153 citations
TL;DR: The range of intersubject variation in the metabolic activation of paracetamol was sixty fold compared with only a three fold variation in glucuronide and sulphate conjugation, which has important implications for susceptibility to par acetamol hepatotoxicity following overdosage especially in a small subgroup showing extensive metabolic activation.
Abstract: The 24 h urinary excretion of paracetamol and its metabolites following a single oral dose of 1.5 g was compared in 111 Caucasians (Scotland), 67 West Africans (Ghana) and 20 East Africans (Kenya). The fractional recovery of the mercapturic acid and cysteine conjugates of paracetamol was 9.3% in the Caucasians compared with only 5.2% and 4.4% in the Ghanaians and Kenyans respectively (P = less than 0.0005). This probably indicates markedly reduced metabolic activation of paracetamol in the Africans. There were no ethnic differences in the sulphate conjugation of paracetamol, but the mean fractional recovery of the glucuronide conjugate in Caucasians (54%) was significantly less than in the Africans (58%). The sulphate conjugation of paracetamol was increased and glucuronide conjugation reduced in Caucasian females compared with males. A similar trend was seen in the Ghanaians but there were no other significant sex differences. The range of intersubject variation in the metabolic activation of paracetamol was sixty fold compared with only a three fold variation in glucuronide and sulphate conjugation. This has important implications for susceptibility to paracetamol hepatotoxicity following overdosage especially in a small subgroup showing extensive metabolic activation. These ethnic differences in paracetamol metabolism may be related to genetic or environmental factors including differences in diet and protein intake.
141 citations
TL;DR: During clinical pharmacology studies with the benzodiazepine antagonist Ro 15-1788 the pharmacokinetic characteristics of high intravenous doses and of an oral dose were examined in six healthy male volunteers, reflecting a dose-proportionality in the areas under plasma concentration-time curves and unchanged distribution characteristics.
Abstract: During clinical pharmacology studies with the benzodiazepine antagonist Ro 15-1788 the pharmacokinetic characteristics of high intravenous doses (20 and 40 mg) and of an oral dose (200 mg) were examined in six healthy male volunteers. Ro 15-1788 was rapidly and extensively distributed in the body with an apparent volume of distribution Vss of 1.06 l kg-1. Elimination occurred rapidly by hepatic metabolism and the high plasma clearance of 1.14 l min-1 resulted in a short elimination half-life of less than 1 h. No difference in the disposition parameters calculated from the data after the 20 and 40 mg doses was observed reflecting a dose-proportionality in the areas under plasma concentration-time curves and unchanged distribution characteristics. Because the blood/plasma distribution coefficient is close to unity the disposition parameters obtained from plasma concentrations are similar to the corresponding parameters with reference to blood. Following oral administration of 200 mg the drug is rapidly absorbed. Peak levels were reached after 20-90 min and were close to or even higher than the values after the 40 mg intravenous dose at the same time point. Due to the high hepatic extraction ratio the fraction reaching the systemic circulation unchanged was reduced to approximately 16% during the absorption step.
137 citations
TL;DR: The data confirm earlier reports that PX is the major metabolite of CA in humans but suggest that Px formation is quantitatively more important than previously believed.
Abstract: Five subjects who participated in an earlier study (Lelo et al., 1986b) of the comparative pharmacokinetics of caffeine (CA) and its primary monodemethylated metabolites paraxanthine (PX), theobromine (TB) and theophylline (TP) were administered CA to steady-state. Using areas under the plasma concentration-time curves for each of the dimethylxanthines derived from CA in the steady-state study and individual plasma clearances of PX, TB and TP determined in the previous study, the fractional conversion of CA to PX, TB and TP and the individual partial clearances of CA have been defined. The mean (+/- s.d.) fractional conversion of CA to PX, TB and TP was 79.6 +/- 21.0%, 10.8 +/- 2.4% and 3.7 +/- 1.3%, respectively. When only demethylation pathways are considered PX, TB and TP accounted for 83.9 +/- 5.4%, 12.1 +/- 4.1% and 4.0 +/- 1.4%, respectively of the CA demethylations. The mean partial clearance of CA to PX was approximately 8-fold and 23-fold greater than those to TB and TP respectively. These data confirm earlier reports that PX is the major metabolite of CA in humans but suggest that PX formation is quantitatively more important than previously believed.
137 citations
TL;DR: The effects of single doses of anhydrous caffeine and placebo on physiological, psychological measures and subjective feelings were studied in nine healthy subjects who had abstained from caffeine-containing beverages for 24 h before each occasion.
Abstract: The effects of single doses of anhydrous caffeine (250 mg and 500 mg) and placebo on physiological, psychological measures and subjective feelings were studied in a double-blind, cross-over study in nine healthy subjects who had abstained from caffeine-containing beverages for 24 h before each occasion. Caffeine and caffeine metabolites in plasma and urine were assayed. Peak plasma concentrations were observed at 1 to 2 h with an approximate half-life of 5 h. The concentrations of the metabolite 1,7-dimethylxanthine increased during the 5 h. The major urine metabolite was 1-methyluric acid. The EEG showed a dose-related decrease in log 'theta' power and a decrease in log 'alpha' power. Other dose-related effects were an increase in skin conductance level (sweat-gland activity) and self rating of alertness. Ratings of headache and tiredness were decreased by the caffeine. The study illustrates the complexities of studying a drug which is widely taken and which is often associated with withdrawal effects.
TL;DR: Zolpidem is likely to prove useful in the management of transient and short-term insomnia in healthy middle aged individuals when impaired performance the next day is to be avoided.
Abstract: Effects of an imidazo-pyridine (zolpidem: 10, 20 and 30 mg) on overnight sleep and on performance the next day were studied in young adults and in middle aged individuals. The young adults were used particularly as an homogenous group to establish any possible adverse effects of the drug on sleep and on performance the next day, and the middle aged subjects with their less restful sleep were used to study efficacy. In the young adults zolpidem led to a marked increase in slow wave sleep with a reduction in stage 2 sleep. There were no significant changes in REM sleep, though there was a tendency for REM sleep to be delayed. In the middle aged there was a reduction in awake activity and drowsy sleep with an increase in stage 2 sleep. The latency to REM sleep was increased but the duration of REM sleep over the whole night was not reduced. Digit symbol substitution and a complex reaction time task were used to study performance, but there were no residual effects with zolpidem (9 h after ingestion). Zolpidem is likely to prove useful in the management of transient and short-term insomnia in healthy middle aged individuals when impaired performance the next day is to be avoided.
TL;DR: This study provides the first direct evidence that interferon inhibits hepatic oxidative drug metabolism in humans and alerts clinicians to the possibility of potentially toxic drug-drug interactions.
Abstract: Antipyrine clearance was measured before and 1 day after administration of a single intramuscular dose of recombinant human leukocyte alpha A interferon. In the nine patients studied, antipyrine clearance was reduced after interferon from 0.49 (0.21-1.13) ml kg-1 min-1 (median (range)) to 0.41 (0.20-1.07) ml kg-1 min-1, P less than 0.01. In individual patients, the decrement in antipyrine clearance was variable, ranging from 5-47% (median, 16%). This study provides the first direct evidence that interferon inhibits hepatic oxidative drug metabolism in humans and alerts clinicians to the possibility of potentially toxic drug-drug interactions.
TL;DR: Cigarette smoking induces a form of P-450 in human liver, responsible for ERDE activity, that contains an epitope recognized by MAb 1-7-1 and is insensitive to MAb 2-66-3 and is not contributing to AHH, CH or ECDE activities of human liver.
Abstract: Four cytochrome P-450 enzyme activities, 7-ethoxyresorufin O-deethylase (ERDE), coumarin 7-hydroxylase (CH), 7-ethoxycoumarin O-deethylase (ECDE) and aryl hydrocarbon hydroxylase (AHH) were measured in human liver needle biopsy samples from smokers and non-smokers. Cigarette smoking was verified and quantitated by measuring plasma cotinine levels. Enzyme inhibitory monoclonal antibodies (MAb) to a 3-methylcholanthrene-induced (MAb 1-7-1) and phenobarbitone-induced (MAb 2-66-3) rat hepatic cytochrome P-450 were used to measure the contribution of MAb-defined, epitope-specific cytochromes P-450 to the total reaction measured for each of the above activities. ERDE activity was significantly elevated in the livers of cigarette smokers, whereas AHH, CH or ECDE activities were not affected by cigarette smoking. No correlation was observed between plasma cotinine concentration and ERDE activity. MAb 1-7-1 inhibited hepatic ERDE activity to a variable extent (from 0 to 65%), but had very little or no effect on AHH, CH or ECDE activities. The inhibitory effect of MAb 1-7-1 on ERDE activity was greater than 50% in the non-smokers. MAb 2-66-3 had no inhibitory effect on any of the enzyme activities studied. In contrast to liver both ERDE and AHH on human placental microsomes from cigarette smokers were inhibited by MAb 1-7-1. The MAb 2-66-3 was without effect. Cigarette smoking induces a form of P-450 in human liver, responsible for ERDE activity, that contains an epitope recognized by MAb 1-7-1. This form of cytochrome P-450 is insensitive to MAb 2-66-3 and is not contributing to AHH, CH or ECDE activities of human liver.
TL;DR: The findings suggest that the cardiovascular toxicity of parenteral chloroquine is related to transiently high plasma concentrations occurring early in the distribution phase, which results from incomplete distribution from a central compartment that is approximately one thousand times smaller than the eventual total apparent volume of distribution at steady state.
Abstract: Chloroquine diphosphate (3 mg base kg-1) was given by constant rate intravenous injection over 10 min to 12 healthy adult male volunteers. Plasma concentrations of chloroquine and the principal metabolite desethylchloroquine, electrocardiograph intervals, and arterial blood pressure were measured at frequent intervals to determine the relationship between cardiovascular effects and plasma concentrations. Peak plasma concentrations ranged between 784 and 6649 (mean 2913) ng ml-1. The decline in plasma concentrations was multiexponential with an initial rapid distribution phase; mean (+/- s.d.) first order rate constant 0.65 +/- 0.14 min-1, and an estimated apparent volume of the central compartment of 0.18 +/- 0.15 l kg-1. There was no serious toxicity, but subjective side effects were reported in all patients and there was a significant fall in systolic blood pressure (110 +/- 9.5 to 101 +/- 12.5 mm Hg; P = 0.03) and rise in heart rate which paralleled the change in plasma chloroquine concentrations. Coincident with changes in blood pressure, there was a significant prolongation of the electrocardiograph QRS interval; 81 +/- 15 to 92 +/- 13 ms (P less than 0.01) but no change in the QTc interval. These findings suggest that the cardiovascular toxicity of parenteral chloroquine is related to transiently high plasma concentrations occurring early in the distribution phase. This results from incomplete distribution from a central compartment that is approximately one thousand times smaller than the eventual total apparent volume of distribution at steady state. Rate of administration is therefore a major determinant of toxicity.
TL;DR: The effects of quinidine at a dose of only 50 mg, on the metabolism of a new drug in EM subjects may prove a useful method of assessing the contribution of the debrisoquine 4-hydroxylase isozyme to the elimination of the drug tested.
Abstract: Quinidine and its diastereoisomer quinine were tested in vitro for their effect on the 4-hydroxylation of debrisoquine, the O-deethylation of phenacetin and the 1'-hydroxylation of bufuralol, by human liver microsomal samples; quinidine was studied for its effect on debrisoquine 4-hydroxylation in vivo. Quinidine was a potent inhibitor of the 4-hydroxylation of debrisoquine and the 1'-hydroxylation of bufuralol, with IC50 values of 0.7 and 0.2 microM, being around 100 times more potent in this respect than quinine. Very much higher (1000-fold) levels of quinidine were required to inhibit the O-deethylation of phenacetin, being rather less potent in this than quinine. Eight subjects were phenotyped for their debrisoquine oxidation status and found to be extensive metabolisers (EM). They were tested again after the co-administration of 50 mg of quinidine with the debrisoquine. The concomitant administration of quinidine increased the metabolic ratios (MRs) by a mean of 26-fold. The effects of quinidine at a dose of only 50 mg, on the metabolism of a new drug in EM subjects may prove a useful method of assessing the contribution of the debrisoquine 4-hydroxylase isozyme to the elimination of the drug tested.
TL;DR: The data indicate that the regulation of cytochrome P-450 isozyme involved in polymorphic debrisoquine/sparteine metabolism is predominantly under genetic control and that enzyme induction exerts only a marginal effect.
Abstract: The effects of antipyrine (1200 mg day-1), phenobarbitone (100 mg day-1) and rifampicin (600 mg and 1200 mg day-1, respectively) administration for 7 days on sparteine metabolism and 6 beta-hydroxycortisol excretion were studied in panels of extensive (EM) and poor metaboliser (PM) subjects. Drug metabolism was induced in both EM and PM subjects by antipyrine and rifampicin pretreatment as indicated by increased excretion of 6 beta-hydroxycortisol. A 30% increase in metabolic clearance of sparteine was observed in EM subjects following rifampicin administration whereas in PM subjects no effect on the overall elimination of the drug was seen. The data indicate that the regulation of cytochrome P-450 isozyme involved in polymorphic debrisoquine/sparteine metabolism is predominantly under genetic control and that enzyme induction exerts only a marginal effect.
TL;DR: Defective hepatic metabolism of midazolam may be a factor in the aetiology of what appears to be a true phenomenon, occurring in 6% of over 200 fit subjects given a standard dose of the drug.
Abstract: The pharmacokinetics of a fixed dose of midazolam (0.3 mg kg-1 i.v.) were studied in detail in 115 healthy patients or volunteers and nine were found with a prolonged elimination half-life. A further 102 patients had an abbreviated pharmacokinetic study, of whom five showed a similar abnormality. Defective hepatic metabolism of midazolam may be a factor in the aetiology of what appears to be a true phenomenon, occurring in 6% of over 200 fit subjects given a standard dose of the drug.
TL;DR: The stereoselectivity of the pharmacokinetic interaction between warfarin and cimetidine was investigated in eight healthy volunteers and resulted in elevation of vitamin K1 2,3-epoxide concentrations, which were similar in each case.
Abstract: The stereoselectivity of the pharmacokinetic interaction between warfarin and cimetidine was investigated in eight healthy volunteers. The warfarin enantiomers were given separately as single doses (15 mg) alone and during chronic administration of cimetidine (1 g day-1). Cimetidine did not interact with S warfarin but there was an interaction with the R enantiomer of warfarin. Cimetidine caused a significant increase in the mean plasma half-life of R warfarin (from 47.8 h to 57.8 h) and a significant decrease in its mean plasma clearance (from 2.3 to 1.7 ml h-1 kg-1) (P less than 0.02). Administration of a pharmacological dose of vitamin K1 together with the enantiomers of warfarin was necessary clinically and resulted in elevation of vitamin K1 2,3-epoxide concentrations, which were similar in each case.
TL;DR: The data presented here are consistent with a two-compartment kinetic model, and it is not known whether the difference in pharmacokinetics is due to chronic therapy or whether it is specific to those patients who show on-off phenomena, but such changes might be related to the development of fluctuations in clinical response.
Abstract: We have studied the clinical effects and pharmacokinetics of levodopa infusions and oral therapy in seven patients with Parkinson's disease They all showed on-off fluctuations whilst receiving long-term treatment with levodopa in combination with a peripheral decarboxylase inhibitor Intravenous infusion at a constant rate for up to 16 h resulted in a smoother clinical response, and maintained plasma levodopa concentrations within narrower limits compared with conventional oral therapy Following infusion rates of 32-80 mg h-1 (05-13 mg kg-1 h-1) the plasma concentration associated with optimum therapeutic response lay between 03 and 16 mg l-1 There was considerable variation in the oral absorption and elimination of levodopa, both within and between subjects The concentration of 3-OMe dopa in plasma hardly increased during each day's levodopa therapy In all cases levels were greater than the maximum concentrations of levodopa, sometimes by as much as a factor of 10 In contrast to most previous reports on the pharmacokinetics of levodopa, the data presented here are consistent with a two-compartment kinetic model It is not known whether the difference in pharmacokinetics is due to chronic therapy or whether it is specific to those patients who show on-off phenomena, but such changes might be related in some way to the development of fluctuations in clinical response
Journal Article•
TL;DR: The results suggest a probable competitive inhibition of oxidative metabolism by neuroleptics, a phenomenon of potential clinical importance both in patients with an inherited poor metabolic capacity and in patients receiving other drugs like beta-adrenoceptor blocking agents and tricyclic antidepressants oxidized by the same enzyme system.
Abstract: Liver oxidative metabolism, assessed by debrisoquine hydroxylation test, was studied in 107 healthy volunteers and in 71 patients with or without neuroleptic drug treatment. The mean metabolic ratio (MR = debrisoquine/4-hydroxydebrisoquine excretion in the urine) was 2.8 +/- 0.1 (s.e. mean) in the control group, six persons being poor metabolizers of debrisoquine (MR greater than or equal to 12.6). The mean MR (12.1 +/- 1.5) was significantly higher in those 42 patients taking neuroleptics than in patients without neuroleptics (0.8 +/- 0.1). In the former group, seventeen patients had a MR exceeding 12.6. Oral contraceptives, antiepileptics, benzodiazepines and progestin derivates did not increase MR values, the highest individual ratio being 2.72 in those subjects not receiving neuroleptics. These results suggest a probable competitive inhibition of oxidative metabolism by neuroleptics. This is a phenomenon of potential clinical importance both in patients with an inherited poor metabolic capacity and in patients receiving other drugs like beta-adrenoceptor blocking agents and tricyclic antidepressants oxidized by the same enzyme system.
TL;DR: The blood pressure fall was significantly greater in the elderly on both treatments and in both erect and supine posture, and was associated with a more prolonged inhibition of plasma angiotensin converting enzyme activity.
Abstract: The pharmacokinetics of angiotension converting enzyme (ACE) inhibitors enalapril (10 mg orally) and its active metabolite, enalaprilat (10 mg intravenously) were studied in nine young healthy volunteers aged 22-30 years and nine sex matched elderly subjects aged 65-73 years. After both drugs, a biexponential curve was fitted to the decline in plasma enalaprilat concentration. Area under the plasma concentration-time curve (AUC) was greater in the elderly for both drugs. Clearance (CL) and clearance/bioavailability (CL/F) were less in the elderly for enalaprilat and enalapril, respectively. There was no difference in F between young (0.62 +/- 0.16) and elderly subjects (0.61 +/- 0.15). Enalaprilat CL and enalapril CL/F were significantly and positively correlated to endogenous creatinine clearance. There was a significant difference in the weight corrected volume of distribution at steady state after enalaprilat between the young and elderly (P less than 0.02). The relationship between plasma enalaprilat concentrations and percentage ACE inhibition, using the Hill equation, showed no difference in the sensitivity to ACE inhibition between the young and the elderly group. The pharmacokinetic differences observed are likely to be related to an age dependent decline in renal function as well as changes in body composition. Kinetic differences partly explain the greater pharmacodynamic response in the elderly.
TL;DR: The pharmacokinetic basis for using various experimental indices, (urinary drug: metabolite and metabolite:drug + metabolite ratios, urinary metabolite recovery and AUC values), for detecting polymorphic oxidative drug metabolism was examined and logarithmic transformation allowed clearer visualisation of the two phenotypic groups.
Abstract: The pharmacokinetic basis for using various experimental indices, (urinary drug: metabolite and metabolite:drug + metabolite ratios, urinary metabolite recovery and AUC values), for detecting polymorphic oxidative drug metabolism was examined. Pharmacokinetic determinants in addition to partial metabolic clearance down the polymorphic route were identified in each index. The ability of the various indices to discriminate bimodality in population data was assessed using a computer simulation. With the exception of the AUC data, bimodality was apparent to varying extents in all of the frequency distributions and, in general, logarithmic transformation allowed clearer visualisation of the two phenotypic groups. Simulated distributions were compared with those observed experimentally for metoprolol and its alpha-hydroxy metabolite. Detailed pharmacokinetic data from controlled studies in small numbers of volunteers can form the basis of the input to the simulation programme. Inspection of the output may help in the design of further studies in larger numbers of subjects in whom only limited data collection is possible.
TL;DR: Par acetamol disposition was studied in groups of pregnant and non-pregnant women of comparable age and there was no difference between the two groups in paracetamol sulphation or renal clearance of unchanged drug.
Abstract: Paracetamol disposition was studied in groups of pregnant and non-pregnant women of comparable age. Paracetamol apparent oral clearance was 58% higher and elimination half-life was 28% lower in the pregnant women compared to the control group. The higher clearance in the pregnant women was due to increased activity of the glucuronidation (75% higher) and oxidative (88% higher) pathways of paracetamol metabolism. There was no difference between the two groups in paracetamol sulphation or renal clearance of unchanged drug.
TL;DR: In patients with cirrhosis, beta-adrenoceptor responsiveness assessed by isoprenaline sensitivity is altered and no correlation was found between noradrenaline or adrenaline concentrations and CD25 values in cirrhotic patients.
Abstract: Isoprenaline sensitivity and plasma catecholamine concentrations were studied to assess the sympathetic nervous activity in 13 patients with alcoholic cirrhosis and were compared with five controls. In patients with cirrhosis, the dose of isoprenaline required to increase the resting heart rate by 25 beats min-1 (chronotropic dose 25 or CD25) ranged from 2.50 to 34.73 micrograms (median: 4.47 micrograms) and was significantly higher than in controls (range: 0.66 to 2.76 micrograms, median: 1.34 micrograms). In cirrhotic patients, CD25 values were significantly correlated with plasma albumin concentration, resting heart rate and wedged hepatic venous pressure. In patients with cirrhosis, plasma noradrenaline concentrations ranged from 192 to 978 pg ml-1 (median: 444 pg ml-1) and adrenaline concentrations ranged from 5 to 183 pg ml-1 (median: 47 pg ml-1). No correlation was found between noradrenaline or adrenaline concentrations and CD25 values in cirrhotic patients. In conclusion, in patients with cirrhosis, beta-adrenoceptor responsiveness assessed by isoprenaline sensitivity is altered.
TL;DR: A clear understanding of the varied pharmacologic properties of the different classes of calcium antagonists is likely to provide a rational basis for the use of these agents in clinical therapeutics.
Abstract: As a class of therapeutic agents calcium antagonists have attracted increasing attention in recent years. Their major indications have been in the treatment of ischaemic myocardial syndromes, certain cardiac arrhythmias, hypertension, obstructive cardiomyopathies, and a number of lesser clinical disorders in which their role is less clearly defined. With the widening spectrum of therapeutic utility and an increasing plethora of newer agents under development, it is of importance to relate the overall pharmacodynamics of individual agents to their clinical effects. Calcium antagonists have a variable specificity for cardiac and peripheral activity. Based on such activity, it is useful to construct a classification of these compounds, new and old, into four categories. Type I agents, typified by verapamil and its congeners (tiapamil and gallopamil) and diltiazem, prolong AV nodal conduction and refractoriness with little effect on ventricular or atrial refractory period. These actions account for their direct antiarrhythmic properties. Type II agents include nifedipine and other dihydropyridines. In vivo, these agents are devoid of electrophysiologic effects in usual doses. They are potent peripheral vasodilators with some selectivity of action for different vascular beds; their overall haemodynamic effects are dominated by this peripheral vasodilatation and reflex augmentation of sympathetic reflexes. Type III agents include flunarizine and cinnarizine (piperazine derivatives), which, in vitro and in vivo, are potent dilators of peripheral vessels, with no corresponding calcium-blocking actions in the heart. Type IV agents are agents with a broader pharmacologic profile (perhexiline, lidoflazine and bepridil); they block calcium fluxes in the heart, in the peripheral vessels, or both. They may inhibit the fast channel in the heart and have other electrophysiologic actions. A clear understanding of the varied pharmacologic properties of the different classes of calcium antagonists is likely to provide a rational basis for the use of these agents in clinical therapeutics.
TL;DR: Comparison of the oral and intravenous data show that doxazosin is completely absorbed in man, mouse and rat and is moderately well absorbed in dog, whereas the drug is extensively metabolized in man and only about 5% of the dose was excreted unchanged in man.
Abstract: 1 The metabolic fate of doxazosin was investigated in man, mouse, rat and dog using 14C-labelled compound. Bioavailability and pharmacokinetic studies were also conducted with non-labelled drug, using a specific h.p.l.c. method.
2 Following both oral and intravenous administration, the major route of elimination of drug-related compounds was via the faeces for all species studied. Comparison of the oral and intravenous data show that doxazosin is completely absorbed in man, mouse and rat and is moderately well absorbed in dog.
3 The drug is extensively metabolized, e.g. only about 5% of the dose was excreted unchanged in man. Metabolism in man mainly involves 6- and 7- O-demethylation and 6′ and 7′-hydroxylation. These and some minor products were common to the mouse, rat or dog and man.
4 Plasma protein binding was high in all species studied, ranging from 95.3% in the rat to 98.3% in human patients.
5 Oral bioavailability is 60% in dog and approximately 50% in the rat, which is similar to the value of 63% reported for man at therapeutic doses. Mean plasma clearance values were 13 ml min-1 kg-1 (dogs), 30 ml min-1 kg-1 (rats) and 1.2 ml min-1 kg-1 (human subjects). Mean plasma half-life values were 5 h in dogs and 1.2 h in rats: a value of 9 h was reported for human volunteers (cf. 2.5 h for prazosin). The long plasma half-life of doxazosin provides the basis for once-daily dosing.
TL;DR: During quinidine treatment, the formation of sparteine metabolites (2- and 5-dehydrosparteine) was practically abolished and patients initially classified as extensive metaboliser thus exhibited the phenotype of poor metabolisers during quinacid treatment.
Abstract: In eight patients a sparteine-test was carried out immediately before and after 1 week of treatment with quinidine 600-800 mg day-1. Before treatment one patient was classified as a poor metaboliser (metabolic ratio: greater than or equal to 20), and seven patients as extensive metabolisers. During quinidine treatment, the formation of sparteine metabolites (2- and 5-dehydrosparteine) was practically abolished. Patients initially classified as extensive metabolisers thus exhibited the phenotype of poor metabolisers during quinidine treatment.
TL;DR: The pharmacokinetics of S-(+)- and R-(-)-mexiletine and of the corresponding conjugates were investigated in six healthy young volunteers after administration of a single 200 mg oral dose of racemic mexiletine hydrochloride and the values for the distribution rate constants and for the elimination half-lives were similar.
Abstract: The pharmacokinetics of S-(+)- and R-(-)-mexiletine and of the corresponding conjugates were investigated in six healthy young volunteers after administration of a single 200 mg oral dose of racemic mexiletine hydrochloride. The values for the distribution rate constants as well as for the elimination half-lives of the two enantiomers were similar but the AUC of the S-(+)-enantiomer was always significantly higher (P less than 0.01) than that of the opposite enantiomer. The mean R/S ratios for unchanged mexiletine in serum and in urine were 0.78 +/- 0.12 (s.d.) and 0.80 +/- 0.21, respectively. Urinary excretion of mexiletine conjugates consisted mainly of the R-(-)-enantiomer; the mean R/S enantiomeric ratio over 48 h was 9.65 +/- 3.10. Serum concentrations of the conjugates were measured in three subjects. The mean R/S AUC ratio was 2.94 +/- 0.48 and the renal clearance of the R-(-)-enantiomer was significantly higher (P less than 0.02) than that of the S-(+)-enantiomer.