Cimetidine-phenytoin interaction: Effect on serum phenytoin concentration and antipyrine test

Summary In a prospective study in nine patients the effects of phenytoin and of cimetidine (1000mg/day) + phenytoin on the antipyrine test and serum phenytoin concentrations were studied. Serum phenytoin increased from the steady state level of 5.7±1.3 mg/l to 9.1±1.4mg/l after three weeks on cimetidine (p<0.01), and fell to 5.8±1.2 mg/l within two weeks after withdrawal of cimetidine. The protein binding of phenytoin was not changed by cimetidine. After use of phenytoin for 2–4 months, antipyrine clearance increased from 0.67±0.06ml/min/kg to 1.61±0.22 ml/ min/kg, and antipyrine half-live fell from 10.9±1.3h to 4.5±0.6h as compared to the values before phenytoin treatment (p<0.01). After three weeks combined use of cimetidine and phenytoin, antipyrine clearance was decreased to 1.01±0.07 ml/min/kg and antipyrine half-life was prolonged to 6.1±0.5h, (p<0.01) compared to the values on phenytoin alone. The distribution volume of antipyrine was not affected by phenytoin nor by cimetidine + phenytoin. The half-life of cimetidine was 2.8±0.3h in the patients on longterm phenytoin treatment. There was a significant positive correlation (p<0.001) between the increase in serum phenytoin concentration and the prolongation of antipyrine half-life caused by cimetidine. Thus, cimetidine increases serum phenytoin concentration, very probably by inhibiting its metabolism. Care should be taken in the concomitant use of cimetidine and phenytoin, and the dose of phenytoin should be modified according to the clinical symptoms and serum phenytoin concentrations.Part of this work was presented at the Joint Meeting of the Scandinavian and German Pharmacological Societies, September 1980 [14]     

The effect of rifampicin on norethisterone pharmacokinetics

Summary The pharmacokinetics of norethisterone have been studied in 8 women during and one month after treatment with rifampicin (450–600 mg/day). Rifampicin caused a significant reduction in the A. U. C. of a single dose of 1 mg norethisterone from 37.8±13.1 to 21.9±5.9 ng/ml X h (p<0.01). The plasma norethisterone half life (-phase) was also reduced from 6.2±1.7 to 3.2±1.0 h (p<0.0025). In one additional woman on long term oral contraceptive therapy the 12 hour plasma norethisterone concentration was reduced by rifampicin from 12.3 ng/ml to 2.3 ng/ml. Rifampicin caused a significant increase in antipyrine clearance, 6-hydroxycortisol excretion and plasma gamma-glutamyltranspeptidase activity but there were no significant correlations between changes in these indices of liver microsomal enzyme induction. There was a significant correlation between the percentage increase in antipyrine clearance and the percentage decrease in norethisterone A. U. C. during rifampicin. The changes in norethisterone pharmacokinetics during rifampicin therapy are compatible with the known enzyme inducing effect of rifampicin.     

Differential induction of antipyrine metabolism by rifampicin

Summary Antipyrine is oxidised to three main metabolites in man. There is evidence that the different metabolites are products of different forms of cytochrome P-450. The effect of rifampicin administration for two weeks on the rates of formation of these metabolites was investigated in healthy volunteers. Rifampicin increased antipyrine clearance and shortened its half-life. Two weeks after stopping rifampicin the induction had largely been reversed. Clearance to all three metabolites was increased by rifampicin. Clearance to 3-hydroxymethylantipyrine was increased from 7.8±0.9 ml/min to 13.3±1.3 ml/min, to norphenazone from 5.8±0.6 ml/min to 19.3±2.1 ml/min and to 4-hydroxyantipyrine from 14.3±2.2 ml/min to 21.9±3.9 ml/min. Thus clearance to norphenazone was increased to a much greater extent than to either of the other two metabolites. It is concluded that this provides evidence for the involvement of at least two different forms of cytochrome P-450 in antipyrine metabolism in man.     

Pharmacokinetics of cimetidine in advanced cirrhosis

Summary The effect of impaired liver function on the pharmacokinetics of cimetidine was studied in 8 patients with advanced cirrhosis given single doses of 100 mg i.v. and 400 mg p.o. on separate days. Compared to a control group of 10 healthy volunteers, the total renal and nonrenal clearance was significantly reduced in the cirrhotic patients; (total plasma clearance mean ± SD) 356±181 vs 789±262 ml/min (p<0.01); renal clearance (Cl_r) 296±100 vs 588±181 ml/min (p<0.01) and nonrenal clearance (Cl_nr) 97±111 vs 205±89 ml/min (p<0.05). Compared to published results for age-matched ulcer patients, both total and nonrenal clearance were lower whereas renal clearance was within the reported normal range. A significant reduction in volume of distribution (V_d) was found, from 2.1±0.1 l/kg in controls to 1.0±0.4l/kg, and in the patient group there was a significant correlation between V_d and total plasma clearance (r=0.72, p<0.05). Volume of distribution in steady state (V_dss) did not differ from published results in age-matched controls. No significant change in half-life was found. Bioavailability, estimated by AUC-measurement, showed considerable patient variability (21–143%), with a mean of 70±39%. This was lower than in the controls. In contrast, measurement of urinary excretion showed higher bioavailability in the patients (66±23 vs 51±8%). No correlation was found between any of the kinetic parameters and the clinical and laboratory data. It is suggested that patients with advanced cirrhosis should be closely observed when given cimetidine, and a reduction in dose should be concidered if side effects are to be avoided.Part of this study has been reported as a Letter to the Editor, N Engl J Med (1982): 307, 187     

Pharmacokinetics of acebutolol in patients with all grades of renal failure

Summary The pharmacokinetics of acebutolol was studied in 10 healthy subjects with normal renal function (RN), in 13 patients with various degrees of renal failure (RI) and in 8 patients undergoing repeated haemodialysis (RD). A highly specific method was used to measure acebutolol (A) and N-acetylmetabolite (NAM). In RN the decrease in plasma levels was biexponential with an apparent plasma half lives in the slow phase of A: 8.8±2.3 h and NAM: 11.4±2.2 h. The percentage of the dose excreted unchanged was 13.9% and as NAM 25.8%. Renal clearances were A: 167±20 ml/min and NAM: 150±18 ml/min. The apparent plasma half life of acebutolol does not change according to the degree of renal insufficiency (RI: 7.0±2.7 h, RD: 7.5±2.7 h), while that of NAM is increased (RI: 21.5±10.1 h, RD: 32.3±16.8 h). There is a linear relationship between the apparent elimination rate constant of NAM and creatinine clearance (r=0.832,p<0.001). In RI 21.7% of the dose is excreted in urine (A 5.0%, NAM 16.7%). When renal function is impaired, the renal clearance of A and NAM decrease in parallel with the creatinine clearance (A: r=0.874,p<0.001; NAM: r=0.954,p<0.001). During dialysis the plasma half life fell (A=3.4±0.9 h, NAM=7.4±2.6 h). The dialytic clearance was A: 42.6±12.7 ml/min and NAM: 40.4±16.3 ml/min, for a blood flow of 238±35 ml/min through a dialyser with a cuprophane membrane (Ultraflo II Travenol). Acebutolol is taken up by erythrocytes (_bc=0.50±0.04). The results suggest that the dosage of acebutolol should be adjusted according to the degree of renal insufficiency.     

Influence of mild thyroid dysfunction on antipyrine clearance and metabolite formation in man

Summary The salivary kinetics and rates of metabolite formation of antipyrine were studied in 6 hyperthyroid and 6 hypothyroid out-patients on 2 occasions, on admission and when T3 and T4 levels had returned to normal after treatment with carbimazole (hyperthyroidism) or l-thyroxine (hyperthyroidism). In hyperthyroidism the half-life of antipyrine was significantly shorter (p<0.05) than after recovery (9.3±1.0 versus 10.6±0.9 h). Hypothyroid patients showed a significantly longer elimination half-life before treatment than after recovery (12.7±2.6 versus 10.3±2.6 h). Antipyrine clearance in hyperthyroid patients was decreased after treatment from 2.7±0.3 to 2.4±0.3 l/h, and it was increased in hypothyroid patients from 2.1±0.4 to 2.5±0.5 l/h (p<0.05). The changes in clearances for the production of the antipyrine metabolites 4-hydroxyantipyrine (OHA), norantipyrine (NORA) and 3-hydroxy-methylantipyrine (HMA) were of the same order of magnitude as total antipyrine clearance, and no selectivity towards any of the metabolic pathways of antipyrine was apparent. Mild thyroid dysfunction seems to affect oxidative drug metabolizing enzyme activity in a non-selective manner and only to a small extent (10–30%). It is suggested that adjustment of the therapeutic regimens of various drugs in mild thyroid disease will only rarely by required on the basis of pharmacokinetic considerations.     

Interaction of bisoprolol with cimetidine and rifampicin

Summary In 6 healthy volunteers the pharmacokinetics of bisoprolol under steady-state conditions was investigated over three consecutive phases: over 7 days of 10 mg of bisoprolol once daily per os, 7 days of 10 mg of bisoprolol once daily plus 400 mg of cimetidine t.i.d. and 14 days of 10 mg of bisoprolol and 600 mg of rifampicin once daily with adequate intervals free of medication. After therapy with bisoprolol alone peak plasma levels (C _max ^ss ) of the beta-blocker were 55.5±6.4 ng/ml (x±SEM), area under the plasma level-time curve (AUC) was 597±70 ng/ml.h, total body clearance (CL) 15.8±1.8 l/h and elimination half-lives (t_1/2) 10.1±1.2 h. Cimetidine did not cause any significant changes in the pharmacokinetics of bisoprolol. Co-administration of rifampicin resulted in a decrease in C _max ^ss (43.0±6.9 ng/ml), AUC (397±54 ng/ml·h) and t_1/2 (6.2±0.4 h). Accordingly, total body clearance increased to 23.8±2.51/h (p<0.05). In conclusion bisoprolol showed a statistically significant but probably clinically not important interaction with the enzyme-inducing drug rifampicin, but not with the enzyme inhibitor cimetidine.     

Pharmacokinetic interactions of timolol with vasodilating drugs,food and phenobarbitone in healthy human volunteers

Summary Pharmacokinetic interactions of oral timolol maleate 10 mg, with food (3566 kJ), single oral doses of prazosin 1 mg and dihydralazine 25 mg, and with a 1 week pretreatment with phenobarbitone 100 mg daily were examined in a randomized crossover study in 12 healthy volunteers. After fasting, the peak level (C_max=29.1±3.2 ng/ml; mean±SEM) was reached at 1.3±0.1 h (T_max). The total area under the serum concentration-time curve (AUC^0–) was 154.4±33.8 ng×h/ml, total clearance (Cl_tot) 751.5±90.6 ml/min, renal clearance (Cl_ren) 97.2±10.1 ml/min, elimination half-life (t_1/2) 2.9±0.3 h and 24-h recovery in urine (X _u ^0–24 ) 11.1±1.4% of the dose. Food and prazosin did not significantly affect the fate of timolol maleate. Dihydralazine enhanced C_max (38.2±4.6 ng/ml) only when compared to phenobarbitone treatment, and did not affect any other parameters. Phenobarbitone pretreatment somewhat lowered C_max (25.5±3.9 ng/ml), AUC^0– (117.5±22.1;p<0.05 vs food) and X _u ^0–24 (8.7±1.2%), evidently by increasing Cl_tot (957.5±116.9 ml/min;p<0.05 vs food), but it did not affect Cl_ren. It is concluded that the pharmacokinetics of timolol maleate can be altered to a limited extent in opposite directions by dihydralazine and phenobarbitone.     

Pharmacokinetics of digoxin in normal subjects after intravenous bolus and infusion doses

Normal subjects were given 0.75 mg of intravenous digoxin as a bolus and a 1-hr infusion, Radio-immunoassayed serum concentrations obtained over 48 hr and urinary excretion rates over 6 days were simultaneously fitted to a two- compartment open model by computer nonlinear least-squares regression. Serum concentration data alone were also fitted by this program. There was good agreement in calculated parameters between the two routes of administration in five of eight subjects, but the infusion mode of administration produced less variability in the apparent pharmacokinetic constants. The half-life values obtained from serum concentration data alone (24.2 hr) underestimated the half-lives obtained by the simultaneous fit (44.1 hr). The steady-state volume of distribution of digoxin averaged 590±164 liters (±1 sd).The renal clearance of digoxin (140±41 ml/min/1.73 m ² )was significantly higher than creatinine clearance (101±13 ml/min/ 1.73 m ² ),indicating tubular secretion of the drug. Digoxin body clearances were 188±44 ml/min/ 1.73 m ² ,indicating elimination of 25% of the dose by nonrenal mechanisms. Urinary excretion data are essential for proper pharmacokinetic analysis of digoxin disposition and reveal a slower rate of elimination than that suggested by earlier studies which determined only serum concentrations.Supported in part by Grant 20852 from the National Institutes of General Medical Sciences, National Institutes of Health.     

Pharmacokinetics of theophylline in infants with bronchiolitis

Summary Single-dose investigations in healthy subjects have demonstrated substantial impairment of renal and extrarenal clearance of digoxin during coadministration of verapamil. A longitudinal study has been performed to assess the changes in digoxin disposition during long-term verapamil therapy. After one week of verapamil 240 mg/d mean plasma digoxin had risen from 0.21±0.01 ng/ml (SE) to 0.34±0.01 ng/ml (p<0.01), and renal digoxin clearance had fallen from 197.57±17.37 ml/min to 128.20±10.33 ml/min (p<0.001). These changes gradually subsided, and after six weeks, renal digoxin clearance had normalized and plasma digoxin had declined to 0.27±0.02 ng/ml (NS). The 24-h urinary recovery of digoxin increased from 46.46±3.23% before to 69.78±3.69% (p<0.001) after six weeks of verapamil co-administration, and this elevation persisted throughout the study. The verapamil-induced suppression of renal digoxin elimination disappears over a few weeks of drug exposure, whereas the inhibition of the extrarenal clearance of digoxin seems to persist.     

Effect of urinary pH on the disposition of methadone in man

Summary The influence of urinary pH on the acute disposition of methadone in man was studied in five healthy volunteers. A cross-over experiment was performed in each subject. In the first experiment the subjects were treated with ammonium chloride (urinary pH 5.2) and in the other the urine was made alkaline (pH 7.8) by treatment with sodium hydrogen carbonate. d, 1-Methadone-HCl 10 mg (M) was administered intramuscularly on each occasion and blood, saliva and urine levels of M were determined by mass fragmentography. Plasma half-lives, volumes of distribution and body clearances of M were calculated in both experiments. The plasma half-lives in the -phase were 19.5±3.6 h (acidic urine) and 42.1±8.8 h (alkaline urine), respectively (p<0.001). The volumes of distribution were increased when the pretreatment was changed from ammonium chloride to sodium bicarbonate, namely from 3.51±0.41 l/kg to 5.24±0.83 l/kg (p<0.01). The body clearance decreased from 134±21 ml/min (acidic) to 91.9±9.1 ml/min (alkaline urine) (p<0.01). The ration M_plasma/M_RBC was about 2.3 and the elimination of M from RBCs was in good agreement with the plasma kinetics of M under both experimental conditions. The salivary levels of M did not reflect the plasma kinetics and considerable variation was seen in the ratio M_saliva/M_plasma (0.26–2.98). Thus, the present experiments demonstrate that pretreatment either with ammonium chloride or bicarbonate had profound effects on both the distribution and elimination kinetics of methadone.     

The short term effects of propranolol, atenolol and labetalol on antipyrine kinetics in normal subjects.

1 The effects of three day courses of propranolol 40 mg three times daily, atenolol 100 mg twice daily and labetalol 100 mg three times daily on antipyrine kinetics were examined in 13 normal subjects. 2 The mean antipyrine clearance initially was 41.3 +/- 12.4 ml/min (mean +/- s.d.) and fell to 35.0 +/- 12.1 ml/min following propranolol (P less than 0.025), 34.5 +/- 9.5 ml/min following atenolol (P less than 0.01), and 35.2 +/- 8.6 ml/min following labetalol (P less than 0.05). 3 The prolongation in antipyrine half-life was significant only following atenolol. Propranolol only caused a significant reduction in the volume of distribution of antipyrine. 4 These adrenoceptor antagonists appear to decrease antipyrine clearance in normal subjects. The reduction in antipyrine clearance was similar with all three drugs and appeared to be independent of the differing lipid solubilities and pharmacological profiles of the adrenoceptor antagonists examined.     

Cirrhosis of the liver markedly impairs the elimination of mexiletine

Summary To study the effects of cirrhosis of the liver on the pharmacokinetics of mexiletine a single i.v. dose of 200 mg was administered to six cirrhotic patients and to six healthy controls. The distribution of mexiletine in both study groups was similar, as indicated by similar values of V₁ and V_ss, but it tended to occur more slowly in the cirrhotics. The plasma protein binding of mexiletine was unchanged in the patients with cirrhosis. The elimination of mexiletine was markedly retarded in the cirrhotics, as indicated by its lower total clearance (2.31 vs. 8.27 ml/kg/h,) lower total elimination rate constant (0.059 vs 0.353 h^–1), and longer elimination half-life (28.7 vs 9.9 h). The antipyrine half-life was 38.3 h in the patients and 14.7 h in the controls. One healthy volunteer had a Morgagni-Stokes-Adams type of syncopal attack 5 min after administration of mexiletine due to disturbance of AV conduction induced by the drug. Thus, on a pharmacokinetic basis the loading dose of mexiletine need not be modified in cirrhotic patients, whereas the maintenance dosage should be reduced to one fourth — one third of the usual dose.     

Effect of Hydralazine on the Elimination of Antipyrine in the Rat

The concomitant administration of hydralazine with metoprolol or propranolol substantially increases the oral bioavailability of these beta-blockers, presumably via reduction of the first-pass effect. It has been suggested that this effect may be secondary to a decrease in the intrinsic clearance of propranolol, possibly by inhibition of oxidative metabolism. To examine the possibility that hydralazine alters oxidative metabolism in vivo, the effect of hydralazine on the pharmacokinetics of antipyrine was examined in the rat. The oral administration of hydralazine hydrochloride, 7.5 mg/kg, 15 min prior to antipyrine administration reduced antipyrine clearance from 9.66 ± 1.18 to 8.19 ± 0.76 ml/min/kg (P < 0.05). Hydralazine was observed to cause substantial hypothermia. The study was repeated in temperature-regulated animals and no alteration in antipyrine clearance was found. Two doses of hydralazine in temperature-regulated rats also failed to alter antipyrine clearance. Thus, it appears that the effect of hydralazine on antipyrine clearance is secondary to the hypothermic effect of hydralazine and not due to a direct inhibition of cytochrome P-450-mediated enzyme activity.     

Short-term ethanol administration impairs the elimination of chlordiazepoxide (Librium®) in man

Summary Ethanol may enhance the sedative effect of benzodiazepines leading to greater psychomotor impairment, but the mechanism is not clear. The present study was carried out to determine the effect of acute ethanol ingestion on the disposition and elimination of chlordiazepoxide (Librium), a widely used benzodiazepine. Five healthy, 22–39-year-old, male volunteers ingested ethanol 0.8 g/kg as 25% in orange juice 1 h before chlordiazepoxide 0.6 mg/kg was injected intravenously. To maintain plasma ethanol concentrations of 50–150 mg/100 ml for 32 h additional ethanol 0.5 g/kg was given orally every 5 h. Plasma clearance of chlordiazepoxide fell from 26.6±2.6 ml/min (mean±SD) without ethanol to 16.6±3.1 ml/min (P<0.05) after ethanol. There was no change in the volume of distribution and therefore the elimination half-life was prolonged from 7.1±1.9 h to 11.8±6.0 h (P<0.05) after ethanol. Ethanol also lowered the plasma binding of chlordiazepoxide from 94.7± 0.6% to 93.4±1.3% (P<0.05). The plasma clearance of unbound chlordiazepoxide fell from 468± 51 ml/min to 264±98 ml/min (P<0.05) after ethanol. The plasma level of the metabolite desmethylchlordiazepoxide was higher and its elimination slower after ethanol. Thus using a pharmacokinetic approach this study has demonstrated that short-term ethanol ingestion in moderate doses impairs the elimination of chlordiazepoxide and accounts, at least partly, for the greater sedation that results when ethanol is taken concomitantly.Supported by the Veterans Administration, NIH Grant AA00267, and the Clinical Research Center of Vanderbilt University School of Medicine     

Pharmacokinetics of tolfenamic acid: Disposition in bile,blood and urine after intravenous administration to man

Summary To study its pharmacokinetics and especially its biliary excretion, ¹⁴C-tolfenamic acid 9.84 µCi/100 mg was infused i.v. in 8 patients with a T-tube inserted in the common bile duct at choledocholithotomy 7–10 days prior to the study. Bile was collected in fractions by continuous suction over a 24 h period. Blood samples were taken and urine collected up to 48 h after the dose. Tolfenamic acid and its metabolites were separated by TLC and were quantitated by liquid scintillation counting. The pharmacokinetics of tolfenamic acid could be described by a two compartment open model with V₁ of 3.67±0.68 l and V_ss of 8.0±1.0 l. The total plasma clearance of tolfenamic acid averaged 106±8 ml/min and t_1/2 was 1.38±0.32 h. A three compartment open model was required to describe the kinetics of total ¹⁴C. The plasma clearance of total ¹⁴C was 15.4±3.9 ml/min and its terminal half life averaged 19.0±4.1 h. The long half-life was caused by the slow elimination of tolfenamic acid metabolites. Four metabolites were measured in plasma and bile. The principal metabolites in bile were glucuronide/sulphate conjugates of hydroxylated derivatives of tolfenamic acid. The recovery of tolfenamic acid in bile was 1.1±0.3% of the dose, whereas the recovery of total ¹⁴C was 18.6±4.9%. The biliary clearances of tolfenamic acid and total ¹⁴C were 1.2±0.3 and 5.0±2.1 ml/min, respectively. Thus, biliary excretion plays a considerable part in the pharmacokinetics of tolfenamic acid.     

Disposition of hexobarbital in intra- and extrahepatic cholestasis in man and the influence of drug metabolism-inducing agents

Summary The pharmacokinetics of intravenously infused hexobarbital was studied in 10 patients with intrahepatic cholestasis and in 9 with extrahepatic biliary obstruction. The results were compared with those obtained in 16 healthy young volunteers and 5 older patients with normal liver function. After infusion, the plasma concentrations showed a rapid initial decline (-phase) and subsequently a slower decrease (-phase). The half-life of a latter phase was 323±84 min in the healthy group, 357±151 min in the patients with intrahepatic cholestasis and 344±115 min in the group with biliary obstruction; the clearances were 3.41±0.90, 4.08±1.95 and 3.81±1.97 ml×min^–1×kg^–1, respectively. The differences were not statistically significant. The mean volume of the central compartment of distribution and the steady state volume of distribution were not significantly different. In two patients hexobarbital clearance during cholestasis was greater than after it had subsided. After treatment of 11 patients with cholestasis with drug metabolism-inducing agents (phenobarbital, rifampicin or phenytoin), the half-life of hexobarbital was significantly shortened and the mean value of hexobarbital clearance was more than doubled.Partly supported by Grant 13-28-22 from The Netherlands Foundation for Medical Research (Fungo).     

Pharmacokinetics of cimetidine and its sulphoxide metabolite during haemodialysis

Summary A single intravenous dose of cimetidine 200mg was administered to 6 patients with severe chronic renal failure one hour prior to haemodialysis. The plasma concentrations of cimetidine and its sulphoxide metabolite at the start of haemodialysis were 2.74±0.12 and 0.76±0.08 µg/ml, and after dialysis for 4h 1.08±0.10 and 0.51±0.08 µg/ml, respectively (mean ± SE). The average haemodialysis clearance (Cl_HDa) of cimetidine during dialysis was 46–92ml/min at a dialysate flow rate of 320ml/min and blood flow rates in the 6 patients between 160–240ml/min. The mean Cl_HDa of the sulphoxide metabolite was 44% higher than that of cimetidine, and ranged between 49–148ml/min. During haemodialysis the mean plasma elimination half-life (t_1/2) of cimetidine was 3.24h (range 2.08–5.08) and of the sulphoxide metabolite 9.49h (range 4.70–14.39). There was a significant relationship between the elimination rate constant () and Cl_HDa of the sulphoxide metabolite (p<0.01), but no such relationship was found between and Cl_HDa of cimetidine. However, there was a tendency to a relationship between of cimetidine and the capacity to metabolise the drug, expressed as the ratio between the plasma concentrations of the sulphoxide metabolite and cimetidine after dialysis for 4h. These ratios ranged between 0.23–0.76, and the lowest ratio was seen in the patient with the lowest value of cimetidine. Thus, the large variations in the plained by differences in their capacity to metabolise the drug. The mean total amount of cimetidine eliminated during dialysis was 27.3mg (range 17.9–31.8), which was 9.0–15.9% of the given dose. Between 12.2–21.2mg (mean 15.3) of the sulphoxide metabolite was eliminated in the dialysate. Major adjustment of the dose of cimetidine on days of dialysis is not necessary.     

Influence of cimetidine on the pharmacokinetics of desmethyldiazepam and oxazepam

Summary The pharmacokinetics of single oral doses of desmethyldiazepam 20 mg or oxazepam 50 mg were studied in 5 healthy volunteers under controlled conditions, before and following a 24 h pretreatment with cimetidine 200 mg×5. Cimetidine significantly impaired (p=0.03) the elimination of desmethyldiazepam, as shown prolongation of its elimination half-life from 51.7±21.9 h to 72.6±39.4 h (mean ± SD), and a decrease in total plasma clearance from 12.0±2.7 ml/min to 8.6±3.3 ml/min. The disposition of oxazepam was not affected. From these results, and recently published data on diazepam and chlordiazepoxide, it is concluded that cimetidine impairs the hepatic elimination of those benzodiazepines which are metabolized by phase I reactions.     

Elimination of azlocillin in patients with biliary t-tube drainage

Summary The pharmacokinetic of azlocillin was followed in five elderly patients after biliary surgery. Total clearance was 138.6±17.7 ml/min when 2.0 g was given as an i.v. bolus injection. The half-life of the -phase averaged 110 min. The total clearance and the half-life of azlocillin were influenced by slight impairment of renal function (creatinine clearance 59.4±13.6 ml/min). In patients with normal liver function biliary excretion of the drug amounted to 5.3±2.8% of the dose (n=3) and the kinetics of biliary excretion were linear. In contrast, in two patients with impaired liver function biliary excretion was 0.2% and 0.5% of the dose, and kinetic analysis of biliary excretion rates revealed at least one zero order step in the excretion process. Renal excretion of the drug amounted to 45.0±17.7% of the dose, which means that 50% of the total clearance of azlocillin has to be accounted for by metabolic clearance.