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The single oral dose kinetics of ethylmorphine and its fractional metabolic clearance by O-dealkylation and N-dealkylation was investigated in five extensive and four poor metabolizers of dextromethorphan. In addition, the urinary metabolic ratios for these pathways (MRO and MRN, respectively) were investigated in a larger group of 27 extensive metabolizers and six poor metabolizers. The mean values for the fractional metabolic clearance by O-dealkylation and the MRO differed significantly between the poor metabolizers and extensive metabolizers without overlap between the values of either of these parameters in the two groups of subjects. In contrast, the corresponding parameters for the N-demethylation did not differ between poor metabolizers and extensive metabolizers. The area under the plasma concentration versus time curve was significantly higher (about three times higher) in the poor metabolizers compared with the extensive metabolizers (p = 0.004). Our data suggest that ethylmorphine is O-deethylated by the cytochrome P4502D6 isozyme inasmuch as both the fractional metabolic clearance by O-dealkylation and the MRO were found to cosegregate with the phenotype for the O-demethylation of dextromethorphan in our group of subjects.

We recently demonstrated that 25 mg of bromfenac, a new nonsteroidal anti-inflammatory analgesic, is at least as effective as 400 mg of ibuprofen in relieving postoperative oral surgery pain. Our objective in this study was to determine whether higher doses were significantly more effective. Two hundred eighty (280) outpatients with postoperative pain after the surgical removal of impacted third molars were randomly assigned, on a double-blind basis, a single oral dose of 10, 25, 50, or 100 mg bromfenac; 650 mg aspirin; 400 mg ibuprofen; or placebo. Subjects rated their pain and its relief for 8 hours. All active treatments were significantly superior to placebo, and bromfenac and ibuprofen were significantly superior to aspirin. The slope of the dose-response curve of bromfenac was significant. The 100 mg bromfenac dose was significantly more effective than the 400 mg ibuprofen dose and had a significantly longer duration of analgesic action.

Eight healthy subjects [who were phenotyped with a debrisoquine (D) hydroxylation test] were selected to cover a wide range in the ratio between D and 4-hydroxydebrisoquine (4-OH-D) in the urine. After a single oral dose of nortriptyline (NT) the metabolic clearance by 10-hydroxylation in the E-position, but not in the Z-position, correlated closely to the metabolic ratio D/4-OH-D (rs = -0.88, p less than 0.01). This indicates that common enzymatic mechanisms are involved in the hydroxylation of D and the E- but not the Z-10-hydroxylation of NT. Slow hydroxylators of NT and D excreted less 10-hydroxynortriptyline in urine and had lower plasma clearance of NT than the rapid hydroxylators. The strong correlation (r = 0.96) between the total plasma clearance of NT and the metabolic clearance by E-10-hydroxylation shows that this metabolic reaction is important in the disposition of the drug.

With data on adults from two previous articles it was found that the average steady-state plasma concentration of verapamil in subjects on long-term oral therapy of 80 mg every 6 hr (Y) correlated strongly with the area under the curve from zero to infinity (AUC0-x/6 (X) where the area refers to that for a single oral dose of 80 mg (Y - 2.41X, n - 15, r - 0.923, P less than 0.001). Steady-state concentrations are predictable from the single-dose data, with an average absolute deviation of 11.1%. We gave seven children (7 to 19 yr old) an initial intravenous bolus dose of 0.1 mg/kg, followed by a 20-min constant rate infusion of 0.007 mg/kg/min. Twenty-four hours after the bolus dose they were put on oral therapy (40 to 80 mg every 6 hr) and 1 mo later the minimum steady-state verapamil plasma concentration (Cminss) was measured. Plasma concentration-time data obtained after the infusion were fitted to biexponential (two sets) or triexponential equations (five sets). The coefficients of the postinfusion polyexponential equations were converted to those for the 0.1-mg/kg bolus dose alone. Mean parameters estimated were: plasma clearance 0.500 l/min, steady-state volume of distribution 279 l, V beta 394 l, half-life 9.17 hr, and mean residence time 10.0 hr. Many correlations were made between the oral Cminss values and functions obtained from the intravenous data. The best correlation was that between Cminss and the predicted steady-state concentration at 3 hr after dosing when bolus doses would be given at 6-hr intervals based on the single-dose intravenous date (r = 0.985, P less than 0.001); this correlation allowed Cminss to be predicted with an average absolute deviation of 10%. Norverapamil was measured in plasma after oral dosing, but was not detectable after intravenous dosing.

The pharmacokinetics of both enantiomers of vigabatrin after a single oral dose in healthy young subjects (mean creatinine clearance 120 ml/min) were compared with kinetics in two groups of elderly subjects, one group aged 60 to 75 years (mean creatinine clearance 86 ml/min) and one group aged 76 to 97 years (mean creatinine clearance 30 ml/min). At a dose of 1500 mg, the group with the eldest subjects and the lowest creatinine clearance values showed mean increases of 3.3-fold in the time to reach the maximum concentration, 2.7-fold in the maximum concentration, and 9.8-fold in the AUC; a twofold prolongation of the t½; and reduced urinary excretion of the biologically and pharmacologically active S(+)-enantiomer. Changes in the intermediate group were qualitatively similar but quantitatively less. Parallel observations were made for the inactive R(−)-enantiomer. Most of these changes can be related to decreased renal clearance of vigabatrin. No interference of either enantiomer in the renal clearance of the other was noted. A nonlinear relationship between renal clearance and creatinine clearance for both enantiomers is suggested. Knowledge of the patient's renal function and an appropriate dose adjustment will minimize side effects during vigabatrin therapy, especially in elderly patients. Clinical Pharmacology and Therapeutics (1988) 44, 558–565; doi:10.1038/clpt.1988.194

The purpose of our investigation was to determine kinetics of naproxen [(+)-6-methoxy-α-methyl-2-naphthaleneacetic acid] relative to its inhibition of PGF2α release during thromhin-induced platelet aggregation in man after a single oral dose of 250 or 500 mg. Naproxen and its metabolite 6-hydroxy-α-methyl-2-naphthaleneacetic acid were measured by high-performance, reversed-phase liquid chromatography with fiuorimetric detection. PGF2α was measured by radioimmunoassay in platelet-rich plasma (PRP). Our subjects were four healthy adult men and five dysmenorrheic women. Peak concentrations of naproxen varied between 26 and 69 µg/ml and half-lifes varied between 9.5 and 21.9 hr, x = 16.4 hr ± 4.4 (SD). Naproxen plasma protein binding exceeded 99.9%. The concentration of the metabolite was less than 1% of naproxen and followed the same plasma concentration profile as the parent compound. The basal concentration of PGF2α varied between 0.13 and 6.3 ng/ml, x = 1.5 ± 1.9 nglml. With no exception, there was a marked decrease in the PGF2α concentration in thrombin-stimulated PRP during therapy, and concentration was inversely correlated to the total plasma naproxen concentration. Clinical Pharmacology and Therapeutics (1981) 29, 168–173; doi:10.1038/clpt.1981.27

The elimination of a single oral dose of theophylline was studied in 12 healthy subjects before and after 250 mg erythromycin every 8 hr for 10 days. Serum theophylline levels were measured by high-pressure liquid chromatography. Mean theophylline elimination half-life rose from 4.79 ± 0.43 hr before to 7.53 ± 0.71 hr after erythromycin. Theophylline clearance decreased from a mean of 91.6 ± 27.0 to 54.8 ± 10.0 ml/kg/hr after erythromycin and the mean apparent volumes of distribution were much the same before and after the antibiotic. The excretion of theophylline and its metabolites was studied in the urine of three of the subjects. In each case the amount of 3-methyixanthine and 1,3-dimethyluric acid decreased after antibiotic. Adjustments of the theophylline dosage may be necessary for patients who take theophylline and erythromycin concurrently to minimize the risk of theophylline toxicity. Clinical Pharmacology and Therapeutics (1981) 30, 422–426; doi:10.1038/clpt.1981.182

Amiodarone serum kinetics after single oral doses and after long-term therapy were investigated in patients with ventricular tachyarrhythmias. When amiodarone was given as a single oral dose (1400 to 1800 mg, n = 6), serum levels of amiodarone and its metabolite, measured by high-performance liquid chromatography, correlated (r = 0.69, P < 0.01). Peak concentrations (amiodarone, 3 to 14 μg/ml; metabolite, 0.7 μg/ml) were attained in 4.9 ± 1.2 hr. Using computer fits to the data, amiodarone mean elimination rate constant and half-life (t½e) were 0.128 ± 0.063 hr−1 and 7.2 ± 5.0 hr. In 12 patients given a mean dose of 1327 ± 338 mg/day of amiodarone for 4.1 ± 2.3 wk, mean serum amiodarone level was 3.84 ± 2.92 μg/ml (range 0.92 to 11.99); in three patients simultaneous determination of concentrations of amiodarone and its metabolite revealed that concentration of the latter was about 50% of that of the parent drug during long-term therapy. In four patients on maintenance therapy (400 to 800 mg/day, serum level 1.08 ± 1.13 μg / ml) drug was discontinued and serum amiodarone levels were determined serially. Serum drug disappearance followed a single exponential function with an elimination rate constant of 0.030 ± 0.012 day−1 and t½e of 29 ± 19 days. Our kinetic data are consistent with the long therapeutic amiodarone tl/2 noted in the treatment of cardiac arrhythmias. Clinical Pharmacology and Therapeutics (1982) 31, 438–444; doi:10.1038/clpt.1982.57

We studied the effect of a single oral dose of the neuronal norepinephrine uptake blocker, desipramine 125 mg, on norepinephrine kinetics. Desipramine reduced the plasma norepinephrine clearance by approximately 20%, from 1.33 ± 0.22 to 1.08 ± 0.19 l/m2/min (p < 0.01). Similarly, plasma norepinephrine clearance was slowed in patients with sympathetic nerves damaged by disease (idiopathic peripheral autonomic insufficiency). Desipramine also reduced the rate of spillover of norepinephrine to plasma, from 0.27 ± 0.07 to 0.15 ± 0.04 µg/m2/min, leaving the plasma norepinephrine concentration unchanged. Disappearance of tritiated norepinephrine from plasma, after infusion to steady state, was biexponential, with half-time of the rapid-removal phase (t1½) = 2.0 ± 0.4 min and half-time of the second exponential (t2½) = 34 ± 10 min. The rapid-removal phase was sensitive to disturbances in the neuronal uptake of norepinephrine, the t1½ being prolonged by desipramine and lengthened in the patients with peripheral autonomic insufficiency. In contrast, the selective extraneuronal norepinephrine uptake blocker, cortisol, 500 mg intravenously, had no effect in normal subjects on either plasma norepinephrine clearance or the t1½ value. Neuronal uptake of norepinephrine contributes to the overall removal of norepinephrine from plasma. Extraneuronal uptake of norepinephrine could not be demonstrated at existing plasma norepinephrine concentrations. Clinical Pharmacology and Therapeutics (1981) 29, 12–20; doi:10.1038/clpt.1981.3

The pharmacokinetics of diltiazem and its major metabolites, deacetyldiltiazem and N-monodemethyl-diltiazem, were studied after single and chronic oral administration in eight patients aged 45 to 69 years with unstable angina pectoris, treated by diltiazem, 120 mg t.i.d. After a single oral dose the time to peak plasma diltiazem concentration was 3.4 (2.1 to 5.0) hours and the elimination half-life was 6.6 hours (4.4 to 10.8 hours). These were unchanged after repeated oral administration (16 to 19 doses). The mean trough (8 hours after administration) plasma diltiazem level after six consecutive doses was 167 micrograms/L (63 to 286 micrograms/L) and was thereafter stable. With chronic administration the AUC increased by a factor of 2.24 +/- 0.31 (SEM; P less than 0.01). Plasma protein binding of diltiazem in these patients ranged from 83% to 93% whereas deacetyldiltiazem binding ranged from 58% to 75%. Plasma protein binding was independent of drug concentration and duration of treatment. Thus an average dose of 120 mg diltiazem given every 8 hours would appear to be a suitable regimen of treatment in most patients with angina pectoris, although users should be aware that there is a significant interpatient variability in steady-state diltiazem concentrations and that a significant accumulation of diltiazem occurs with chronic therapy.

A single oral dose of 300 microng of clonidine lowered systolic blood pressure by 20 +/- 4 mm Hg and diastolic blood pressure by 13 +/- 4 mm Hg in five healthy normotensive subjects (controls). Heart rate fell from 56 +/- 2 to 52 +/- 2 beats/min. In six tetraplegic subjects with physiologically complete chronic cervical spinal cord transection above the level of the sympathetic outflow, the same dose of clonidine did not significantly lower either systolic or diastolic blood pressure. Heart rate fell from 67 +/- 4 to 53 +/- 2 beats/min. Peak plasma concentrations of clonidine, measured by mass fragmentography, and elimination of the drug from plasma were similar in tetraplegic and control subjects and there was no difference in the incidence of the principal side effects of clonidine--sedation and dry mouth. Although the number of subjects studied is small, the absence of a fall in blood pressure after clonidine in the tetraplegic subjects suggests that the hypotensive action of clonidine in man is dependent on intact descending bulbospinal pathways and is mediated by withdrawal of sympathetic tone and provides direct evidence that some antihypertensive drugs may lower blood pressure in man by a direct action on the brain.

The metabolic ratios (MRs) between debrisoquin and 4-hydroxydebrisoquin in urine after a single oral dose of 10 mg debrisoquin were bimodally distributed in 757 healthy, white Swedish volunteers. Forty-one subjects (5.4%) had an MR greater than 12.6 and were classified as slow debrisoquin hydroxylators. The MR was reproducible in urine stored at +8 degrees C for 1 week and at -20 degrees C over a period of 5 years. Collection intervals of 6 or 12 hours gave the same MR. Intraindividual repeatability of the debrisoquin phenotyping test was established in 37 subjects examined twice at least 2 weeks apart. The calculated frequency of the single allele that is believed to control deficient debrisoquin hydroxylation is similar among white Swedish people, as among other white groups examined so far; however, it is significantly different from the frequency in certain Oriental groups. Detailed comparisons of the prevalence of slow debrisoquin hydroxylation in different ethnic groups are not possible due to shortcomings in current epidemiologic techniques used (small materials, the location of the antimode distinguishing rapid and slow hydroxylators unknown, and family studies missing).

The optieal enantiomorphs of warfarin were studied in 10 normal sub;ects. Eaeh sub;ect was given in separate experiments a single oral dose of R(+) warfarin, S(-) warfarin, and the racemate, R,S(±) warfarin, in the amount of 1.5 mg of drug per kilogram of body weight. The biologie half-life for (+) warfarin, (-) warfarin, and raeemie warfarin was 58 ± 5, 33 ± 4, and 42 ± 2 hours, respeetively, a highly significant differenee (p < 0.01) between the enantiomorphs. The blood level of drug for (+) warfarin was 94% greater than that tor (-) warfarin. The area under the pro thrombin time curve plotted logarithmically showed a 76% greater effect for (-) warfarin than for (+) warfarin. Thus, the intrinsic activity of (-) warfarin was 3.4 times as great as thot of (+) warfarin in the induction of hypoprothrombinemia. A high degree of direct correlation was found between the area for the blood level of drug and the hypoprothrombinemic effect for both the (+) and (-) warfarin enantiomorphs. It is concluded that the greater intrinsic activity of (-) warfarin than (+) warfarin does not result primarily from the blood level of the enantiomorphs but may result from a difference in permeability or affinity for the receptor site.

Our goal was to compare and contrast in the same normal twins the relative contribution of genetic and environmental factors to large interindividual variations in the metabolism of acetaminophen (APAP) and antipyrine. These drugs were selected because they are biotransformed by different mechanisms. A single oral dose of APAP (10 mg/kg) was given to six sets of monozygotic (MZ) and six sets of dizygotic (DZ) twins. All were normal, nonsmoking, nonmedicated, and male. Among these 24 subjects, there were 300% interindividual variations in rate constants for formation of the sulfate and glucuronide conjugates, as well as in the overall rate constant for APAP elimination. Intratwin variations for each measurement were as target within MZ as within DZ twinships, suggesting that predominantly environmental rather than genetic factors maintained interindividual variations. Two other observations support this conclusion: Intraindividual variations were frequently as large as interindividual variations, and regardless of zygosity for twins living together, intratwin correlation coefficients were almost twice those of twins living apart. Quite different results were obtained when these twins received antipyrine. After a single oral dose of antipyrine (18 mg/kg), 500% interindividual variations in rate constants for formation of the three main oxidative metabolites of antipyrine appeared to be mainly under genetic control. Also for antipyrine and its principal metabolites, intraindividual variations were much smaller than interindividual variations. In contrast to the results with APAP, regardless of zygosity, intratwin correlation coefficients for antipyrine were similar for twins living apart and twins living together. This comparison between APAP and antipyrine metabolism in the same carefully selected normal twins under apparently uniform environmental conditions reveals that interindividual variations in APAP metabolism arise from certain unidentified environmental factors, whereas genetic factors cause the large interindividual variations that occur in antipyrine disposition. Clinical Pharmacology and Therapeutics (1984) 36, 417–430; doi:10.1038/clpt.1984.199

Subjects (n = 45) were randomly given single oral doses of 2 (n = 11), 3 (n = 9), 5 (n = 8), 10 (n = 10), or 15 mg/kg (n = 7) chloroquine base. Chloroquine was analyzed by HPLC in serum samples taken at 3 to 168 hr after dosing. AUCs, calculated for the time period of 0 to 168 hr were proportional to the doses. Mean AUC value increased 6.7 times when the dose was increased 7.5 times (from 2 to 15 mg/kg). These data do not support the existence of significant capacity-limited chloroquine elimination within the dose range studied.

The concentration of diazepam in the plasma and saliva of 9 normal human subjects receiving a single oral dose of diazepam (10 mg) over an 8-hr period was determined by gas-liquid chromatography/electron capture analysis. In addition, the binding of diazepam to plasma protein in these subjects was determined using equilibrium dialysis at specific time intervals corresponding to periods of plasma and saliva collection. A linear relationship was found between diazepam concentration in plasma and that in both mixed and parotid saliva, over plasma concentrations ranging from 196 ± 16.4 to 74.8 ± 10.3 ng/ml. The elimination constants (−Ke) were 0.13, 0.17, 0.18 for diazepam disappearance from plasma, parotid saliva, and mixed saliva, respectively. The mean parotid concentration ratio was 0.035 and the mixed saliva/plasma diazepam concentration ratio was 0.029. These were not affected by variations in plasma diazepam levels. The percentage of the plasma diazepam concentration in both parotid saliva (3.5%) and mixed saliva (2.9%) was of the same order as the fraction of diazepam found to be free from plasma protein in these subjects (2.0% to 3.5%). The results indicate that there is no significant difference between parotid saliva and mixed saliva concentrations over a period of 8 hr after a single oral dose of diazepam. The results strongly suggest that the appearance of diazepam in saliva may provide an alternate, non invasive method of determining plasma diazepam levels.

To compare the effects of intravenous and oral verapamil we examined the prolongation of the PR interval in 11 patients after (1) a single 10 mg IV bolus given over 2 min, (2) a single oral dose of 120 mg, and (3) a sustained concentration-maintaining infusion. Maximal PR interval prolongation was delayed relative to peak plasma verapamil concentration in all patients after the bolus and in seven of 11 patients after oral dosing. In all 11 patients oral verapamil was less potent than a single intravenous bolus of verapamil; the plasma verapamil concentration corresponding to a 10% prolongation of the PR was 39.5 ± 21.7 ng/ml after the bolus and 146.3 ± 75.1 ng/ml after the oral dose (P = 0.001). However, there was no such difference between oral verapamil and an infusion in six patients. The plasma verapamil concentration corresponding to a 10% PR prolongation was 35.7 ± 24 ng/ml after the bolus, 132.5 ± 80.8 ng/ml after the oral dose, and 85.2 ± 29.9 ng/ml after the infusion. Maximum PR prolongation (drug efficacy) was comparable for the three methods of administration. There was no evidence of tachyphalaxis during prolonged infusions. We conclude that both oral doses and infusions of verapamil are less potent than bolus doses, but that drug efficacy at the concentrations reached is equivalent for the three. Plasma verapamil concentrations determined after bolus doses appear to underestimate effective plasma concentration when the drug is given by the oral or infusion methods. Clinical Pharmacology and Therapeutics (1982) 32, 711–720; doi:10.1038/clpt.1982.227

Normal male volunteers on xanthine-restricted diets had a plasma theobromine (TB) half-life (t1/2) of 6.1 +/- 0.7 hr (mean +/- SEM), a TB metabolic clearance rate (MCR) of 113.8 +/- 6.8 ml/min (mean +/- SEM), and an apparent volume of distribution (aVd) of 59.9 +/- 7.8 L (mean +/- SEM) after a single oral dose of 6 mg/kg of TB. A two-week period of dietary abstention from methylxanthines shortened the mean plasma TB t1/2 by 33% and increased the mean MCR of TB by 59%, no change occurred in mean aVd of TB. In another experiment, normal male volunteers received the same oral dose of TB for each of five consecutive days. The mean plasma TB t1/2 measured immediately after the last TB dose was prolonged by almost two-thirds, while the mean aVd increased 23%. Although the mean plasma TB t1/2 measured four days after this last TB dose was the same as that measured after a single oral dose, the mean MCR of TB increased by 34%, but this change was balanced by increased mean aVd of 35%. These results suggest that immediately after five daily doses of TB, an impairment of TB clearance occurs that is reversible by four days of dietary abstention from methylxanthines.

The kinetics of nalidixic acid (NA) and its two metabolites, 7-hydroxynalidixic acid (HNA) and 7-carboxynalidixic acid (CNA) were studied after a single oral dose and after two doses a day for 7 days. Total unconjugated NA, HNA, and CNA concentrations in plasma and urine samples were assayed by a new high-pressure liquid chromatographic (HPLC) technique. NA was rapidly absorbed and hydroxylated to HNA. Both were rapidly excreted in urine with an apparent elimination half-life (t1/2) of 6 to 7 hr. CNA was never detected in the plasma, although it accounted for about 25% of total urinary NA and metabolites. No major sex-related differences in the kinetics and the metabolic pattern were observed. During the 7-day treatment there was no significant cumulation of NA and HNA. The study demonstrated that the concentration of the active compounds, unconjugated NA and HNA, was more than five times the minimum bacteria inhibiting concentration for 8 hr after drug and slightly above this concentration during the next 4 hr.

The antihypertensive effects of prazosin in relation to its kinetics were studied after single doses (intravenous and oral, 0.5 mg) and during increasing multiple doses (0.5 to 5 mg three times a day). There was a fall in systolic and diastolic blood pressures of 10% to 14%, which was greater in the standing than in the sitting position. Prazosin plasma concentrations correlated with dose (P less than 0.001). After intravenous prazosin the fall in systolic and diastolic blood pressure and prazosin plasma concentration correlated (P less than 0.01) during the beta-elimination phase in all patients. In only five of eight patients, however, did mean plasma concentration and antihypertensive effect during continuous treatment with different doses correlate. The maximal fall in systolic blood pressure correlated (P less than 0.01) with that after the first oral steady-state dose (0.5 mg three times daily), which indicates limited possibility of early identification of prazosin responders. There were no signs of overshoot of blood pressure when prazosin was withdrawn for a week. On rechallenge with a single oral dose of 2.5 mg prazosin there were no signs of enhanced hypotensive effect.

The disposition of a single parenteral or single oral dose of amitriptyline was followed in seven young (mean age 22 yr, range 21 to 23) and five elderly (mean age 71 yr, range 62 to 81) healthy men. The mean systemic clearance did not change with age (10.8 +/- 2.1 ml/min/kg in elderly and 12.5 +/- 2.3 ml/min/kg in young subjects). Mean t 1/2 was longer in the older (21.7 +/- 2.9 hr) than in the younger group (16.2 +/- 6.1 hr) as a result of an increase in the volume of distribution (17.1 +/- 2.4 and 14.1 +/- 2.0 l/kg). The bioavailability and the fraction of the drug bound to plasma proteins did not change with age. Single doses of amitriptyline were not well tolerated clinically by either elderly or young subjects, which confirms the need for a gradual buildup in the therapeutic regimen and for close clinical surveillance of elderly depressed patients treated with amitriptyline.

Eleven Ghanaian and 12 Swedish subjects phenotyped with a debrisoquine (D) hydroxylation test were given a single oral dose of nortriptyline (NT). Much the same percentage of the given NT dose was excreted as 10-hydroxy-NT (10-OH-NT) by Ghanaians (43.1%) and Swedes (49.2%). There was a close correlation between plasma clearance of NT by 10-hydroxylation and the D metabolic ratio (D/4-OH-D in urine) in the Ghanaians (rs = −0.95; P < 0.01) and Swedes (rs = −0.84; P < 0.01). The E-isomer of 10-OH-NT is the major isomer in both Ghanaians (76% to 92% of total 10-OH-NT) and Swedes (78% to 95%). It is suggested that the E-10-hydroxylation of NT and the 4-hydroxylation of D are similarly coregulated in Ghanaians and Swedes. Clinical Pharmacology and Therapeutics (1984) 36, 374–378; doi:10.1038/clpt.1984.190

Clonazepam (CZP) was measured in the plasma of eight subjects for 48 hr after a 0.03-mg/kg oral dose. After pretreatment for 19 days with phenytoin (DPH, 4.3 mg/kg/day), plasma CZP concentrations were determined in the same subjects after another 0.03-mg/kg oral dose of CZP. The same protocol was followed in eight additional subjects using phenobarbital (PB, 1.4 mg/kg/day) instead of DPH. DPH pretreatment lowered mean plasma CZP concentration in 8 of the 12 time points. DPH pretreatment increased CZP clearance by 46% to 58% and decreased CZP half-life (t½) by 31%. Both changes were statistically significant. After PB pretreatment the mean plasma CZP concentration was lowered by an average of 11%, but the decrease was statistically significant for only 1 of the 12 time points. PB decreased mean CZP t½ by 11% and increased CZP clearance by 19% to 24%, but only the increase in clearance was statistically significant. Both DPH and PB increased CZP clearances and decreased the areas under the plasma concentration-time curves without altering the volumes of distribution. This observation is consistent with induction of CZP metabolism. The overall effect of DPH (4.3 mg/kg/day) was greater than the effect of PB (1.4 mg/kg/day). Neither the DPH or PB had a significant effect on the extent of CZP protein binding. Clinical Pharmacology and Therapeutics (1980) 28, 368–375; doi:10.1038/clpt.1980.175

Analogue, digital, and hybrid computers may be used in two principal ways in the analysis of data from pharmacokinetic studies: (1) for rapid numerical analysis of data and (2) for pharmacokinetic simulation. Simulation may be defined as the act of building a model of a system and observing its performance. In pharmacokinetics, the equations and models elaborated are always oversimplifications and their appropriateness can only be iudged by their ability to describe the observed data and the accuracy with which they make predictions of future observed data. Five examples are employed to illustrate the use of computers; the paths from the original observed data to the final answers are shown in detail. The examples are as folIows: (1) the relationship between the area under the lincomycin serum concentration curve and the dose of lincomycin administered intramuscularly; (2) the distribution of the half-lives of the antibiotics lincomycin and novobiocin; (3) prediction of multiple dose serum levels of lincomycin observed after constant rate intravenous infusions with an analogue computer; (4) the fitting of serum levels of tetracycline observed after a single oral dose with a two-term exponential equation; (5) simulation of serum levels produced by depointramuscular preparations of lincomycin with a digital computer.

A dose-response curve for oral codeine phosphate was established in 12 adult male patients with chronic cough. The response measured was the per cent reduction in cough counts following 4 doses of codeine as compared to placebo. The curve of response on the log of the dose used was found to be linear, and a single oral dose of 15 to 20 mg. of codeine seemed to be optimum under the conditions of this study. No correlation between the objective cough counts and the patient's subiective evaluation of the drugs was established.

The relative contribution of genetic and environmental factors to maintaining twofold differences in rates of ethanol elimination from plasma was examined in 14 sets of nonmedicated, nonhospitalized healthy twins. After a single oral dose of 1 ml. per kilogram of 95 per cent ethanol, intrapair differences in rates of elimination were less in identical than in fraternal twins. Thew results indicate that individual differences in rates of ethanol elimination among the 28 twins were genetically controlled and that environmental factors played a negligible role. In 6 prisoners in solitary confinement, rates of ethanol metabolism increased in 3 but declined in the remaining 3 after 21 days of ethanol administration. Rates of antipyrine elimination from plasma were accelerated by ethanol administration in each of the 6 volunteers. Considerable individual variation occurred in the degree to which ethanol shortened plasma antipyrine half-lifes; reduction ranged from 4 to 37 per cent of the initial antipyrine half-life. These results suggest that ethanol administration for 21 days at this dosage fails to alter consistently the rate of its own metabolism but increases antipyrine metabolism in all subjects to varying extents.