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The effect of metronidazole, at a dose of 1.2 g daily, on theophylline disposition was studied in 10 healthy adult volunteers. Neither theophylline half-life, volume of distribution nor total body clearance was altered by the anti-microbial. It is concluded that metronidazole does not impair theophylline metabolism despite the fact that it is a substituted imidazole. [ABSTRACT FROM AUTHOR]

Background: Aspirin, with its analgesic, anti-inflammatory, antipyretic, and anti-platelet actions, is one of the most frequently used drugs. Although its use as prophylaxis against thromboembolism is well established, an optimal dose, conferring maximal anti-platelet action without increased risk of bleeding, remains elusive., Method: We assessed the possible pharmacokinetic contribution to this problem in 107 healthy, non-medicated volunteers. Serum aspirin esterase activity was evaluated at 37 degrees C with 1 mM aspirin as substrate. On the basis of the report that most of aspirin esterase activity is accounted for by pseudocholinesterase, we additionally quantified the activity of this enzyme, with and without dibucaine as an inhibitor, using Ellman's reaction, in 41 of our volunteers., Results: Aspirin esterase activities in all of our volunteers (33.90 nmol/ml/min to 222.65 nmol/ml/min, median 103.45 nmol/ml/min) showed a continuous and skewed distribution with eight outliers. In the 41 subjects so studied, aspirin esterase activities correlated positively with both pseudocholinesterase activities (Spearman's rho=0.593, p<0.001) and dibucaine numbers (Spearman's rho=0.422, p<0.01)., Conclusions: Our results support previous observations that the rate of aspirin hydrolysis is not determined by aspirin esterase alone and that other factors are probably involved. Additionally, the skewed distribution of aspirin esterase activities makes a case for its possible contribution to the phenomenon of aspirin resistance.

Background: Pseudocholinesterase polymorphism, as an example of pharmacogenetics with important clinical implications, has been widely studied and documented. However, data on a sample Irish population is lacking. We sought to provide this., Method: In an assay involving Ellman's reaction, pseudocholinesterase activity, alone and with dibucaine or fluoride as an inhibitor, was quantified using propionylthiocholine iodide as substrate., Results: Pseudocholinesterase activities of 1.13-12.71 U/ml (mean +/- SD 6.74 +/- 2.04 U/ml) showed a normal distribution among our 116 healthy, non-medicated volunteers, aged 11-80 years (30.7 +/- 10.5 years) and weighing 46-114.6 kg (66.8 +/- 11.4 kg). However, dibucaine numbers from an inhibition study yielded a trimodal pattern consistent with the hypothesis of two allelic genes. Using an established nomenclature, 92 (79.3%) of our volunteers were homozygous for the usual form of the enzyme (E1uE1u). Of the 13 genotyped as E1uE1a, it is possible that 3 were misclassified and are probably E1kE1a. Only one volunteer was homozygous for the atypical form of the enzyme, with activity of 1.13 U/ml and dibucaine and fluoride number of 18.2 and 82.8, respectively., Conclusion: The continuous variation in pseudocholinesterase activity and the trimodal pattern of dibucaine numbers are both in accord with observations in other population groups. Although dibucaine number yields a trimodal pattern, its use could lead to misclassification of some E1kE1a as E1uE1a.

1. We undertook a temporal study of external sodium-stimulated lithium efflux (sodium-lithium countertransport) in erythrocytes and blood pressure by measuring these two parameters in three phases of the menstrual cycle (menstrual, midcycle and luteal phases) in 22 healthy, non-medicated females with regular menstrual cycles. Plasma oestradiol and progesterone levels were also determined. 2. Sodium-lithium countertransport activity (activity in 140 mmol/l external NaCl) in the midcycle phase (0.176 +/- 0.017 mmol h-1 l-1 of cells) was lower than in the menstrual (0.192 +/- 0.016 mmol h-1 l-1 of cells, P < 0.030) and luteal (0.203 +/- 0.018 mmol h-1 l-1 of cells, P < 0.030) phases. The Vmax of the transporter changed similarly but the K(m) was unaltered. 3. The plasma oestradiol level was 628.9 +/- 39.1 pmol/l in the midcycle phase, higher than in the menstrual (232 +/- 18.5 pmol/l, P < 0.001) and luteal (372.5 +/- 28.1 pmol/l, P < 0.001) phases. The progesterone level was 28.6 +/- 2.1 nmol/l in the luteal phase, and values were lower in the menstrual (2.5 +/- 0.3 nmol/l, P < 0.001) and midcycle (2.8 +/- 0.4 nmol/l, P < 0.001) phases. 4. There was no correlation between plasma oestradiol and sodium-lithium countertransport activity or Vmax during the menstrual cycle, but plasma progesterone was positively correlated with sodium-lithium countertransport activity (r = 0.478, P < 0.025, n = 22) and Vmax (r = 0.551, P < 0.045, n = 14) in the luteal phase. 5. Systolic blood pressure did not change significantly during the menstrual cycle. However, the diastolic pressure showed variation similar to that in sodium-lithium countertransport activity/Vmax, its midcycle value of 66.6 +/- 1.4 mmHg being lower than that in the luteal (71.6 +/- 1.3 mmHg, P < 0.025) and menstrual (70.6 +/- 1.4 mmHg, P < 0.025) phases. 6. We conclude that sodium-lithium countertransport activity exhibits catamenial variation. Therefore we suggest, given this observation, that blood sampling for the assessment of the state of activity of the transport system be standardized in relation to a phase of the menstrual cycle in future studies involving females.

The effect of a single dose of alcohol (0.8 g/kg), given with "diet coke," on erythrocyte sodium-lithium countertransport (SLC) in relation to membrane cholesterol and phospholipids was assessed over 24 h in 10 healthy volunteers. Baseline passive lithium efflux (0.168 +/- 0.008 mmol l-1 Cell H-1) was increased 1 h (0.202 +/- 0.014 mmol l-1 cell h-1; p < 0.030), and 4 h (0.200 +/- 0.014 mmol l-1 cell h-1; p < 0.020), but similar to that at 24 h postalcohol (0.173 +/- 0.011 mmol l-1 cell h-1). These changes were not associated with any change in intracellular lithium. Control SLC VMAX of 0.387 +/- 0.054 mmol l-1 cell h-1 fell at 1 h (0.328 +/- 0.050 mmol l-1 cell h-1; p = 0.0012) and 4 h (0.312 +/- 0.048 mmol l-1 cell h-1; p < 0.0005). Its value 24 h postalcohol (0.371 +/- 0.047 mmol l-1 cell h-1) was comparable to that at baseline. There was no significant change in the affinity of the transporter for external sodium throughout the experimental period, suggesting that the reduction in VMAX 1 and 4 h after alcohol ingestion resulted from a noncompetitive inhibition. Intracellular sodium 4 h after alcohol was lower than at baseline, but returned to the control value within 24 h. In a control group (n = 5), pretreatment with "diet coke" alone did not alter any of the measured parameters. It is concluded that alcohol pretreatment increases passive lithium efflux and decreases SLC Vmax. Both effects are evident up to at least 4 h postdosing, but recover within 24 h in the absence of further alcohol intake.

The activity of the human erythrocyte sodium-lithium countertransport (SLC) is stable over long periods in individuals. However, it is becoming increasingly evident that the transport system is susceptible to modulation, both acutely and chronically, by various factors. In this study, the authors observed temporal variation in SLC over a period of 10 h (08.00-18.00 hours) in healthy volunteers. SLC Vmax was maximum (0 center dot 354 +/- 0.051 mmol L-1 cell-1 h-1; mean +/- SE) at 'mid-day' and significantly higher than in the morning (0 center dot 291 +/- 0 center dot 035 mmol L-1 cell, h; P < 0 center dot 010). Its value in the evening (0 center dot 316 +/- 0.042 mmol L-1 cell-1 h-1) was lower than at 'mid-day' (P < 0 center dot 045) but higher than in the morning (P < 0 center dot 037). These changes were not accompanied by any significant change in the affinity of the transporter for external sodium, Km. Changes in SLC Vmax did not correlate with the corresponding ones in either plasma cortisol or aldosterone. However, they correlated well with those in plasma renin activity, the correlation between mid-day and a.m. sets of values (r = 0 center dot 718; P = 0 center dot 019) being better than that between mid-day and p.m. (r = 0 center dot 688; P = 0 center dot 028). The authors conclude that changes in SLC occur during the day, and this need be taken into account in the planning and execution of studies involving determination of the activity of this transport system.

To assess a possible acute effect of environmental factors on sodium-lithium countertransport (SLC), we determined the activity of this transport system in 14 healthy volunteers, who are nonhabitual drinkers, before and 1 hour after intake of alcohol (0.8g/kg) with "Coke" as the vehicle. Alcohol significantly increased the "leak pathway" component of lithium efflux from a baseline value of 0.21 +/- 0.02 to 0.24 +/- 0.02 mmol/Lcell.h(p < 0.003); and reduced the Vmax of the transporter (0.38 +/- 0.05 to 0.31 +/- 0.04mmol/Lcell.h;p < 0.0005) without significantly changing its affinity for external sodium. The reduction in Vmax was dependent on the initial activity of the transporter (r2 = 0.5). A plot of reduction in Vmax against the product of initial Vmax value and blood alcohol level in each subject revealed a stronger relationship (r2 = 0.86), suggesting that the observed change in Vmax was also dependent on blood alcohol level. Coke alone did not change any of the parameters. We conclude that alcohol acutely inhibits SLC as well as alters erythrocyte membrane in a manner that increases passive lithium efflux.

On the basis of a preliminary observation that sodium-lithium countertransport showed different intra-individual variations when calculated by two standard methods despite using the same sets of lithium efflux data, we decided to compare values by the two methods in a much larger number (50) of volunteers. Although there was significant correlation between the two sets of values (r = 0.936), mean value by M-1 was significantly higher than that by M-2 (P < 0.007). Using appropriate statistical methodology, the limits of agreement between M-1 and M-2 values (-0.066 to 0.096 mmol L cell-1 h-1) were considerable; and the 95% confidence limits of the bias (i.e. mean difference) did not include zero. Furthermore, neither the 95% confidence interval for the correlation coefficient nor that for the slope of regression line included 1.0. These suggest lack of agreement between the two sets of values. The probable cause of this difference is discussed.

On the basis of reports that some calcium channel blockers impair the elimination of some drugs, the effect of nifedipine on the disposition of antipyrine and theophylline was assessed in healthy volunteers. Antipyrine half-life of 10.04 +/- 1.43 h (mean +/- SD) after a week intake of nifedipine (20 mg twice daily) was not significantly different from the control value of 10.64 +/- 2.15 h; nor was that of 10.02 +/- 1.49 h after 2 weeks pretreatment with the calcium channel blocker in eight healthy volunteers. Control antipyrine clearance (ml min-1) of 44.40 +/- 10.58 was not significantly different from that of 45.66 +/- 9.34 and 46.87 +/- 9.63 after nifedipine pretreatment of 1 and 2 weeks, respectively. Similarly volume of distribution was unaltered: 0.601 +/- 0.074, 0.591 +/- 0.078 and 0.602 +/- 0.051 l kg-1, respectively. A week pretreatment with nifedipine did not significantly alter either of theophylline half-life (7.32 +/- 0.81 h (control) to 7.50 +/- 0.80 h) or clearance (42.10 +/- 5.84 ml min-1 (control) to 43.77 +/- 4.00 ml min-1) in six volunteers. However the change in volume of distribution: 0.451 +/- 0.053 l kg-1 (control) to 0.483 +/- 0.062 l kg-1 was significant (p less than 0.025). Generally, theophylline plasma levels were lower after nifedipine pretreatment and the difference was significant at 2 and 4 h post-dosing (p less than 0.05). It is suggested that nifedipine, unlike diltiazem and verapamil, is unlikely to interfere with the functional integrity of the hepatic mixed-function oxygenase enzymes, but might displace theophylline from plasma protein.

On the basis of reports that diltiazem binds to the hepatic microsomal enzymes and inhibits the metabolism of coadministered drugs, we investigated the effect of a 240 mg daily dose of the calcium channel blocker for a week on theophylline metabolism in 8 healthy male volunteers aged 20-24 years and weighing 56-68 kg. None of theophylline half-life (9.7 h), volume of distribution (0.514 l.kg-1) and total clearance (0.63 ml.min-1.kg-1) after pretreatment differed from the respective control value of 9.5 h, 0.519 l.kg-1 and 0.65 ml.min-1.kg-1. In 6 of the volunteers, 600-mg daily dose of rifampicin for a week induced theophylline metabolism. The control half-life of the bronchodilator (9.6 h) was reduced to 5.5 h and its total clearance (0.64 ml.min-1.kg-1) increased to 1.22 ml.min-1.kg-1. There was no change in volume of distribution. In these 6 volunteers, intake of diltiazem (240 mg daily), concurrently with rifampicin for a week, significantly elevated theophylline half-life to 6.2 h as well as reduced its clearance to 1.03 ml.min-1.kg-1. The volume of distribution did not change. Furthermore, diltiazem-induced absolute fall in theophylline clearance correlated significantly with its post-rifampicin value (r = 0.895). It is suggested that diltiazem has no effect on theophylline metabolism in non-induced subjects. However, rifampicin-induced metabolism of the bronchodilator could be attenuated by diltiazem when the two drugs are given concurrently.

On the basis of the reports that beta-adrenergic stimulation affects gastrointestinal motility in man as well as induces N-acetyltransferase in rat pineal gland, we decided to assess the effects of salbutamol pretreatment on the absorption as well as disposition of sulphamethoxazole (SMZ). After a control pharmacokinetic study of SMZ, each of six healthy volunteers took salbutamol at a dose of 4 mg four times daily for two weeks, and the kinetic study of SMZ was repeated after the morning dose on the fifteenth day. None of SMZ half-life, volume of distribution, renal and hepatic clearance rates was significantly altered. However, salbutamol pretreatment resulted in significant reduction in the absorption rate constant of SMZ from 1.168 +/- 0.509 h-1 (mean +/- S.D.) to 0.688 +/- 0.348 h-1 (P less than 0.025), and this was associated with prolongation of tmax from 3.00 +/- 1.69 h to 4.33 +/- 1.51 h (P less than 0.025). Cmax, however, was not correspondingly reduced probably as a result of significant increase in the extent of SMZ absorption from 611 +/- 108 mg to 749 +/- 78 mg (P less than 0.025). Our findings suggest that beta-adrenergic stimulation does not significantly induce human hepatic N-acetyltransferase enzyme. However, it does reduce the absorption rate as well as increase the extent of absorption of SMZ.

The effect of erythromycin stearate at a dose of 1 g daily on theophylline disposition was studied in six healthy adult males. The mean value of 5.46 h for the theophylline half-life after 48 h pretreatment with erythromycin stearate was not significantly different from the control value of 5.24 h. The half-life value of 8.48 h after a 1-week course of the antibiotic, however, represented a significant increase (p less than 0.005). Theophylline disposition 1 week after the last dose of the antibiotic was not significantly different from the control. It is suggested that therapeutic doses of erythromycin stearate for a week or more could impair the disposition of concurrently administered theophylline. The impairment however, is reversible, being absent a week after the last antibiotic dose.

The effect of placebo or cimetidine at a dose of 1 g daily on theophylline elimination was studied in a double-blind control manner in twelve healthy adult males aged 19-31 years. In a group of six, placebo had no effect on any of theophylline half-life (t1/2), volume of distribution (Vd), and total body clearance (CL). In another group of six, theophylline t1/2 rose significantly from 5.48 to 9.04 h (p less than 0.001) after 48 h and to 8.98 h (p less than 0.001) after a week pretreatment with cimetidine. Correspondingly, CL (ml min-1kg-1) fell to 0.66 (p less than 0.025) and 0.60 (p less than 0.01). Changes after 48 h pretreatment were not different from those after a week pretreatment. Seven days after the last cimetidine dose, theophylline disposition had reverted to the control level. There was no significant change in Vd. In five elderly subjects aged 56-68 years, a week of dosing with cimetidine caused a rise in t1/2 (7.17 h to 10.39 h; p less than 0.001) and a fall in CL (0.77 ml min-1kg-1 to 0.53 ml min-1kg-1; p less than 0.005) without significantly altering Vd. In two subjects, there was restoration of theophylline disposition to the control level 72 h after cessation of cimetidine intake. Changes in the elderly were not significantly different from those in the younger ones. Data indicate that cimetidine-induced impairment of theophylline disposition is of rapid onset, has rapidly attainable maximum effect, and is rapidly reversible. Furthermore elderly individuals are just as susceptible to it as the younger adults.

Chlorothiazide absorption was studied in five healthy adult males at 1,000, 750, 500 and 250-mg dose levels. The 24-hour-absorbed fraction fell from a mean value of 20.15% of the orally administered dose at the 250-mg level to 8.38% at 1,000 mg. Analysis of data at the four dosage levels for each subject is suggestive of the fact that chlorothiazide absorption is possibly an example of Michaelis-Menten kinetics. Possible factors responsible for the saturable absorption are discussed.

Twenty Nigerians with labile essential hypertension (LEH) were asked to record their blood pressure and pulse rate for 14-16 hours using the Remler Portable Ambulatory Blood Pressure Recorder while exposing themselves to the stress of Lagos traffic. The average blood pressure (systolic and diastolic) and pulse rate for the test day (ASBP, ADBP and APR) were determined in a cross-over randomised open design before (C), after one week on placebo bidaily (P1), after one week on bromazepam 1.5 mg bidaily (B), after one week on placebo bidaily (P2) and after one week on labetalol 100 mg bidaily (L). Allocation to the active drugs was randomised. All drugs were administered at 8.00a.m. and 8.00p.m. respectively. The maximum blood pressure (systolic and diastolic) and pulse rate MxSBP, MxDBP and MxPR were similarly determined. Both B and L significantly reduced ASBP, ADBP, APR, MxSBP, MxDBP and MxPR but L produced a much greater reduction in the above parameters than B. Side effects observed included drowsiness with B (two subjects) and postural dizziness with L (one subject). Both drugs were effective in controlling LEH but L was more effective than B in reducing stress hypertension.

Renal effects of nifedipine were assessed in 3 groups of healthy normotensive volunteers. In the first group (N = 10), a single 20-mg dose of the slow-release formulation caused an increase in 8-h sodium excretion (P less than 0.025) and urine volume (P less than 0.005). Natriuresis (P less than 0.05) and diuresis (P less than 0.05) were still evident after 1 wk of pretreatment, but were significantly attenuated (P less than 0.05), in each case, compared to levels after a single dose. Natriuresis and diuresis after 2 wk of intake were indistinguishable from control levels. In another group of 8, a single 10 mg dose of the conventional formulation (capsule) effected natriuresis (P less than 0.01) and diuresis (P less than 0.001) similar to those associated with intake of a single 20-mg dose of the slow-release formulation. Natriuresis and diuresis associated with a 20-mg single dose of the conventional formulation were not different from control but were less than those following intake of the 10-mg dose (P less than 0.025 in each case). In the third group of 6, nifedipine, though weaker than chlorothiazide, promoted natriuresis (P less than 0.025) and diuresis (P less than 0.025) of the thiazide without augmenting its kaliuresis. In all the groups, there were no changes in creatinine clearance, and nifedipine did not alter kaliuresis. It is suggested that natriuretic and diuretic effects of nifedipine in healthy normotensive individuals are dependent on the dose employed, the formulation used, and the duration of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of beta-adrenoceptor blockers on the absorption and elimination of the diuretic chlorothiazide was studied in healthy subjects. A week of pretreatment with either pindolol (10 mg twice daily) or propranolol (80 mg twice daily) resulted in significant reduction in 36 h mean cumulative urinary recovery of chlorothiazide in two groups of six subjects compared with a control (untreated) group. A week of pretreatment with atenolol (100 mg daily) did not significantly alter 36 h cumulative urinary excretion in another group of six subjects. None of the beta-blockers significantly changed chlorothiazide half-life. It is suggested that the non-selective (as opposed to the cardioselective) beta-blockers reduce chlorothiazide absorption by the mechanism(s) discussed.

On the basis of the report that benzimidazoles bind to and inhibit the hepatic cytochrome P-450 enzyme system, the effect of mebendazole and albendazole on theophylline disposition was studied in 12 volunteers. Mebendazole at a dose of 100 mg b.d. for 3 days did not significantly alter the theophylline half-life, volume of distribution or clearance in a group of six. In another group of six adult volunteers, albendazole (400 mg) pretreatment did not alter the same parameters. However, in this second group, pretreatment with cimetidine (400 mg t.d.s. for 5 days) significantly increased theophylline half life from 7.7 to 9.8 +/- 1.5 h (P less than 0.001) and reduced its clearance from 0.8 to 0.60 +/- 0.1 ml min-1 kg-1 (P less than 0.005). The volume of distribution was not altered significantly. It is concluded that at therapeutic doses it is unlikely that mebendazole or albendazole will induce theophylline toxicity if co-administered with the bronchodilator. Cimetidine-induced impairment of theophylline metabolism is such that toxicity will be more likely in individuals with initial high theophylline clearance.

We investigated the effect of 4 days pretreatment with cimetidine (1.2 g daily) and ranitidine (0.3 g daily) on tolbutamide disposition in an open randomised, cross-over study design involving 8 healthy adult male volunteers. Control half-life of tolbutamide 6.29 h was not significantly altered by cimetidine (6.93 h) or ranitidine (6.97 h). The corresponding apparent oral clearance (ml.min-1.kg-1) were not significantly different: 0.26 (control), 0.24 (cimetidine) and 0.25 (ranitidine). Apparent volume of distribution was also unaltered 0.140 l.kg-1 (control), 0.141 l.kg-1 (cimetidine) and 0.146 l.kg-1 (ranitidine). It is suggested that the hepatic monooxygenase isozyme that catalyses the rate-limiting conversion of tolbutamide to its hydroxy derivative is not susceptible to the inhibitory effect of cimetidine or ranitidine.