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Ciprofloxacin is widely reported to lower theophylline clearance in patients. Since cyclosporin and theophylline are metabolized by cytochrome P-450 enzymes in the human liver, we investigated whether ciprofloxacin could alter the pharmacokinetics of cyclosporin in healthy volunteers. There was no significant difference (P greater than 0.05) in the pharmacokinetic parameters estimated for cyclosporin without and during ciprofloxacin administration. The results of the present study suggest that ciprofloxacin is unlikely to affect the pharmacokinetics of cyclosporin to a clinically important extent at a dosage of 500 mg twice a day.

The effects of morphine on the single dose pharmacokinetics of theophylline were examined in two groups (6 rats/group) of male Sprague-Dawley rats after the administration of theophylline (6.25 mg/kg) alone and in conjunction with a 5 mg /kg I.V. dose of morphine sulfate. Concomitant morphine administration resulted in a 55 % reduction in theophylline clearance (0.14 ± 0.04 vs. 0.31 ± 0.061 · h−1 kg−1; p. < 0.0005). The reduction in theophylline clearance with morphine administration was accompanied by a significant prolongation in theophylline half-life (3.5 ± 1.5 vs. 1.4 ± 0.35 h; p < 0.02). No changes in the volume of distribution of theophylline occurred with co-administration of morphine. The mechanism of this pharmacokinetic interaction may be partially related to competition between theophylline and morphine for enzymes which metabolize these compounds.

Pentylenetetrazole (75 mg/kg) induced a characteristic coarse body tremor (accompanied by limb extension) and hyperactivity in 4-day-old rat pups. These effects were reversed by diazepam (0.5 and 2 mg/kg) but not by CL 218, 872 (10 and 20 mg/kg) which is selective for type 1 benzodiazepine receptors. Diazepam did not affect the brain concentrations of pentylenetrazole, indicating that the reversal was not based on a pharmacokinetic interaction. Neither diazepam nor CL 218,872 had significant effects on the behavior of the rat pups, although diazepam (2 mg/kg) tended to increase locomotor activity. The results suggest that diazepam displays an anticonvulsant effect in the neonatal rat which is mediated by type 2 receptors.

A LARGE and clinically important interaction between digoxin and quinidine is now well documented.1 2 3 4 5 The cardiac glycoside digitoxin is extensively used in clinical practice, but its interaction with quinidine has not been definitively evaluated.6 , 7 In this study, which assessed the pharmacokinetic interaction of digitoxin with quinidine, we found that simultaneous administration of quinidine had no statistically significant effect on the distribution or clearance of intravenously administered digitoxin. Methods Ten healthy male and female volunteers participated after giving informed consent (Table 1). Their ages ranged from 23 to 32 years. None had evidence of medical disease, and none were taking medications . . .

Eight patients aged 57-86 years with non-insulin-dependent diabetes mellitus (NIDDM) taking long-term glibenclamide treatment (5-15 mg/day) were given oral trimethoprim-sulphamethoxazole due to an acute bacterial infection. After 4-6 days of combined treatment, the total plasma glibenclamide concentrations were determined every second hour for 12 h, and the area under the curve (AUC) was computed. A second plasma glibenclamide profile was obtained 2-4 weeks after withdrawal of trimethoprim-sulphamethoxazole. The levels of plasma glibenclamide did not differ between the two occasions, nor did the simultaneously determined levels of blood glucose and plasma insulin. It is concluded that there is no consistent pharmacokinetic interaction between glibenclamide and trimethoprim-sulphamethoxazole in NIDDM patients.

Although a reduction in blood ethanol concentration has been proposed to mediate the ethanol antagonist activity of naloxone observed in clinical and experimental situations, an increase in this variable as well as in brain ethanol concentration has been found in rats treated with naloxone (0.5 and 2.0 mg/kg, i.p.) ten min after intragastric administration of ethanol (1 and 2 g/kg). This effect disappeared either when naloxone was administered 50 min after ethanol or when ethanol was given intraperitoneally. On the other hand, naloxone induced a slight but significant slowing in intestinal transit rate. These results suggest that naloxone may facilitate gastrointestinal absorption of ethanol when administered soon after an oral load of this drug. Therefore, mechanisms other than a pharmacokinetic interaction appear to be involved in the antagonist action of naloxone.

1. Possible interactions between cilazapril and hydrochlorothiazide with respect to pharmacokinetics and renal effects were investigated in healthy subjects (single dose) and in hypertensive patients (multiple dosing). 2. No significant pharmacokinetic interaction was found between cilazapril and hydrochlorothiazide. 3. Cilazapril showed weak saluretic properties as compared with hydrochlorothiazide, but increased the saluretic effects of hydrochlorothiazide. 4. Cilazapril attenuated the hypokalaemia observed with hydrochlorothiazide in hypertensive patients. 5. The effect on blood pressure reduction obtained from the combination of cilazapril and hydrochlorothiazide lasted longer than that of cilazapril alone.

Male Wistar rats exposed intermittently to 300 ppm (12.5 mumol/l) morpholine vapour 5 days a week for 6 h daily during 4-15 weeks displayed an increasing brain solvent content analyzed by a sensitive gas chromatographic method. Rats drinking water which contained 150 mg NaNO2/l during the vapour exposure period showed initially larger brain solvent concentrations which began to decrease after 8 weeks. Fat solvent concentrations were a fraction of those detected in brain of the solvent-exposed animals or of those in the combined exposure. Nitrite exposure alone caused decreased spinal cord axon acetylcholine esterase activity after 8 weeks while this effect was noted in the combined exposure only at 8 weeks disappearing later on. Axonal succinate dehydrogenase activity was below the controls in the combined exposure throughout the study, and combination also caused persistent increase in the muscle creatine kinase activity. The morpholine-induced effects were less remarkable. The results point at pharmacokinetic interaction between the solvent and nitrite with its own effects on energy metabolism. No N-nitrosomorpholine was found although other metabolic interactions could not be excluded.

1 The potential for a pharmacokinetic interaction between digoxin and cimetidine was investigated in a series of studies. 2 In a single-dose cross-over study in healthy volunteer subjects cimetidine increased the area under the plasma digoxin concentration curve and the peak plasma digoxin concentration. 3 In a repeated-dose study in healthy volunteer subjects taking digoxin 0.25 mg daily, co-administration of cimetidine resulted in an average increase in plasma digoxin concentration of 0.15 ng/ml. 4 In a repeated-dose study in healthy volunteer subjects taking digoxin 0.5 mg daily, co-administration of cimetidine resulted in an average increase in plasma digoxin concentration of 0.19 ng/ml. 5 In a repeated-dose study in patients receiving long-term digoxin therapy for atrial fibrillation co-administration of cimetidine had no significant effect on plasma digoxin concentrations. 6 We have shown that co-administration of cimetidine and digoxin in volunteer subjects causes a statistically significant but small increase in plasma digoxin concentration but no such increase was found in patients. We conclude that it is doubtful that this interaction is of any clinical significance.

Furosemide gains access to its intraluminal site of action by active secretion by the organic acid transport system of the proximal tubule. Inhibition of this transport by probenecid would predictably decrease the effect of furosemide. In this study in 8 normal volunteers, however, the opposite occurred; namely, pretreatment with probenecid increased the overall response to furosemide by prolonging its effect. Sodium excretion in 8 hr due to 40 mg of furosemide rose from 262 +/- 16 to 358 +/- 11 mEq after probenecid. Urine volume increased from 3,265 +/- 275 to 4,165 +/- 183 ml after probenecid. Analysis of the time-course of the increased diuresis and natriuresis showed that probenecid actually decreased the response for the first 60 to 90 min after furosemide but increased the subsequent response sufficiently to result in a greater overall effect. Possible explanations include access of furosemide to its active site from the serum, an effect of probenecid on prostaglandin transport, and a changing pharmacokinetic interaction between probenecid and furosemide.

Clinically relevant drug interactions leading to toxicity are discussed with emphasis on the mechanism of action and clinical implications. No attempts are made to cover the whole field of drug interactions. Instead, the problems are illustrated by examples of pharmacodynamic and pharmacokinetic interactions described in the literature of veterinary and human medicine.

Co-administration of cannabidiol with delta1-tetrahydrocannabinol was found to have no effect on the rate of disappearance of delta1-tetrahydrocannabinol from the blood of rats. The implications of this finding are discussed.

Based on results of studies of a possible terfenadine-theophylline interaction on file with Merrell Dow, Inc., a randomized, crossover study was undertaken to determine if there were a pharmacokinetic interaction between these two medications. Seventeen normal volunteers were randomized to receive theophylline or a theophylline-terfenadine combination for 14 days, followed by a 2-week washout period, with crossover to the other treatment for 14 days. Serum theophylline concentrations were measured on the last day of each treatment phase for determination of pharmacokinetic parameters. No differences were found in elimination rate constant, elimination half-life, area under the concentration-time curve, time to peak concentration, or maximum theophylline concentration. It is concluded that concomitant terfenadine therapy does not affect the pharmacokinetic profile of theophylline in healthy male volunteers.

It is often recommended that acetylsalicylic acid (ASA) and dipyridamole should be given together in order to obtain secondary prophylaxis against certain ischaemic diseases. Therefore, the possible pharmacokinetic interactions between these agents were assessed following single-dose exposures in 14 healthy volunteers. The plasma concentrations of ASA, salicylic acid (SA) and dipyridamole were measured by selective h.p.l.c. techniques. It was found that, while dipyridamole kinetics were unaffected by concurrent ASA, concurrent dipyridamole significantly enhanced the peak concentration (24%) and AUC (27%) of ASA. Thus, co-administered dipyridamole might influence the anti-platelet effect of ASA.

Pharmacokinetic studies were carried out in mice after co-administration of 2-nitroimidazoles with differing prototropic properties: Ro 03-8799, misonidazole, SR 2508, and azomycin. In addition, the distribution of sensitizers in different areas of individual tumors, as well as several normal tissues were measured after intravenous dosing of 0.5 mmol kg-1 (145-56 mg/kg). Although there appeared to be no significant pharmacokinetic interaction between sensitizers after co-administration, there was a significant difference in the distribution of sensitizers within tumors of differing type and size. In small, fast growing SaFa and large, slow growing CaRH tumors, the levels of all sensitizers was relatively constant throughout. However, large fast growing SaFa tumors demonstrated the high degree of variability in the Ro 03-8799 concentration that is seen in the clinic. This may be important in the modelling of human tumors with regard to sensitizer distribution.

In order to examine a potential interaction between isoxicam and propranolol, single 200 mg doses of isoxicam were administered to ten healthy male volunteers before and during treatment with propranolol, gradually attaining a dose of 80 mg t.i.d. for 11 days. The pharmacokinetic profiles of the isoxicam plasma concentration/time data obtained over 96 h following the doses of isoxicam before and during propranolol administration were compared. No significant change was found in any of the pharmacokinetic parameters determined. These results suggest that propranolol has no effect on the metabolic disposition of isoxicam.

1. A gas chromatographic method was applied to study plasma levels of perphenazine (PPZ) and its major metabolites in man before and during simultaneous antiparkinson treatment. Twenty-six psychotic patients received various forms of PPZ administration as well as antiparkinson drugs. 2. Biperidine (5 mg) was administered intravenously to each of five patients, who 5 days earlier had had a single dose of PPZ-enanthate i.m. No significant alterations in plasma concentrations of PPZ were observed. 3. In fourteen patients receiving oral PPZ treatment the plasma levels of PPZ and its metabolites did not deviate significantly from controls after addition of biperidine or orphenadine given for 3 weeks in fixed oral doses. 4. The ratio between PPZ plasma concentration measured 4 and 7 h after the morning dose was not affected by concomitant antiparkinson therapy. 5. It is concluded that no clinically relevant pharmacokinetic interaction takes place between PPZ and two generally used antiparkinson drugs during steady-state conditions in psychotic patients.

Clavulanate potentiated ticarcillin contains two components with an established safety record. Ticarcillin used clinically alone and with clavulanate, a component of clavulanate potentiated amoxycillin, given orally or intravenously. No pharmacokinetic interaction occurs between the two components when given together in man or animals in which metabolism is qualitatively similar to man. Safety evaluation studies carried out in the animals established as suitable for studying the toxicology of ticarcillin have shown no unexpected synergistic or antagonistic toxic effects of Timentin not predicted from the toxicological evaluation of clavulanate alone. Reproductive mutagenic, cardiovascular and general pharmacological studies have shown no significant hazard from Timentin. Clinical experience with ticarcillin has been reviewed, and impairment of platelet function, seen at supratherapeutic doses, has been shown in an animal model not to be influenced by clavulanate. The assessment of the safety of ticarcillin and clavulanate for therapeutic use in man is thus comprised of the clinical experience with ticarcillin and parenteral clavulanate in clavulanate potentiated amoxycillin, animal safety evaluation studies, and the clinical experience with Timentin reported in this symposium.

Nifedipine, metoprolol and atenolol were administered orally to young, healthy volunteers. Each drug was given alone and nifedipine was also given with both beta-adrenoceptor blockers. Each drug was given for 3 days immediately before the study days. Plasma and urine drug concentrations were measured and the relevant pharmacokinetic parameters calculated. No pharmacokinetic interaction between nifedipine and the beta-adrenoceptor blockers was revealed.

The elimination kinetics and anticoagulant effect produced by single 1.5-mg/kg doses of ( R ) - (+) - ,( S ) - ( − ) - ,and racemic warfarin were determined in 10 healthy men. The results obtained in experiments with the individual enantiomers were used to predict the elimination kinetics and anticoagulant effect of racemic warfarin, assuming that there is no interaction between the two enantiomers. These predictions were compared to experimental results, and no significant differences were observed. This finding suggests that there are no pronounced pharmacokinetic or pharmacodynamic interactions between single large doses of ( R ) - (+) and ( S )-(−)-warfarin in humans.

We have investigated the influence of cimetidine on the disposition of tolbutamide in 7 healthy subjects, who received 250 mg tolbutamide daily for 4 days followed by the concomitant intake of cimetidine 400 mg twice daily for a further 4 days. Cimetidine had no effect on the disposition of tolbutamide, including the unbound hydroxylation clearance rate (324 ml X min-1, tolbutamide alone; 316 ml X min-1, tolbutamide plus cimetidine). The total urinary recovery of carboxy- and hydroxy-tolbutamide metabolites was 85.7 +/- 20.3% of the dose when tolbutamide was given alone and 78.9 +/- 14.3% when given with cimetidine. This lack of a pharmacokinetic interaction suggests selectivity of cimetidine-induced inhibition of Phase I drug oxidation.

In order to elucidate the mechanism of ajmaline-quinidine interaction previously observed in humans, the effects of quinidine on pharmacokinetics of ajmaline were investigated in rats. Concurrent oral administration of 10 mg/kg of quinidine markedly increased the plasma concentration of ajmaline at a dose of 2 mg/kg. On the other hand, it did not affect the pharmacokinetics of ajmaline after intravenous dose. The availability of ajmaline after oral dose showed an increase from 13% to nearly 100% by the presence of quinidine, which suggests a change in the presystemic clearance of ajmaline. In fact, when ajmaline was administered into the intestinal loop, its concentration in mesenteric venous plasma increased approximately 5-fold by the combination with quinidine. Furthermore, quinidine delayed the elimination rate of ajmaline from the perfused rat liver. These results indicate that quinidine prevents presystemic elimination of ajmaline in the intestine and liver, and increases the systemic availability of ajmaline.

Objectives To assess potential pharmacokinetic (PK) interactions between atazanavir (ATV, 300 mg, once daily) and lopinavir (LPV, 400 mg, twice daily), both boosted by ritonavir (RTV, 100 mg). Design Two-parallel groups, addition of LPV in patients receiving ATV ( n=6), and addition of ATV in patients receiving LPV ( n=7), with before/after comparisons. Methods Each group had two complete PK profiles before and 2 weeks after the addition of the second protease inhibitor (PI). Total plasma concentrations (Ctot) were analysed by HPLC-UV and unbound plasma concentrations (Cu) and cellular concentrations (Ccell) were analysed by LC-MS/MS. Plasma and cellular PK parameters were also calculated. Unbound and cellular fractions were expressed as Cu/Ctot and Ccell/Ctot ratio. Data were analysed by paired Student t-test on log values; correlations between Ccell, Cu and Ctot were explored by log-log linear regression. Results Adding LPV to ATV did not influence the plasma and cellular PK parameters of ATV. Adding ATV to LPV was associated with a decrease in LPV concentrations (by 16% for area under the time-concentration curve, maximum concentration and trough concentration, NS; and by 35% for Cmin, P=0.04). The RTV PK parameters remained unmodified. The Ccell/Ctot and Cu/Ctot ratio was unaffected by the addition of the second PI and remained stable throughout dosing interval. Good correlations were observed between Ccell, Cu and Ctot for each drug. No relevant toxicity was observed. Conclusions Adding LPV to ATV did not influence the plasma and cellular PK parameters of ATV. Adding ATV to LPV caused a limited decrease in LPV concentrations. The clinical significance of this decrease is unknown and warrants further investigation to determine the need for tailoring LPV dosage in selected cases.

The serum and red blood cell (RBCs) disposition of epirubicin (EPR) after intravenous bolus injection without and with coadministered quinine (QUI) was investigated in patients undergoing a cyclic chemotherapy with EPR. QUI possesses a statistical significant influence on the EPR serum concentrations and, as a consequence, on the pharmacokinetic parameters for the initial distribution phase of EPR. Within the first 15 min after administration, EPR was distributed from the central compartiment distinctly faster in compare to the control, when QUI was preadministered (t1/2 = 6 min for the control group and t1/2 = 3 min with QUI; -46% , p < 0.05). Yet, in the beta-phase when drug-elimination predominates, no statistical significant influence of QUI in regard to EPR serum and RBC concentrations could be observed. Half-life of elimination was 9.5 h for the control group and 8.6 h for the QUI group (-10% ). The mean initial serum concentration (c0) was reduced significantly by QUI from 7359 ± 506 ng/ml to 4351 ± 1682 ng/ml (-42 % . p < 0.005). Furthermore. QUI caused a reduction of the serum bioavailability of EPR (expressed as AUC0-24-values) from 3404 ± 1008 ng/ml × h to 2359 ± 1073 ng/ml × h (-3 1 % , p < 0.05). Vd and Vdß were increased at about 90% and the mean total body clearance was accelerated from 45.3 to 148.7 ml/min, but due to the large standard deviations the calculated difference for these parameters was not statistically significant. In the observed time interval of 24 h, the red blood cell coefficient of distribution kRBC of EPR was lower if QUI was coadministered (kRBC = 1.25 ± 0.12 for the control group kRBC = 1.15 ± 0.13 under QUI; p < 0.04). The results point out that QUI induces an accelerated distribution of EPR from the blood into the tissue and that QUI additionally may have influence on the red-blood cell partitioning of EPR.

In the present study, Diabecon (D-400), a herbomineral anti-diabetic preparation, was studied for its pharmacokinetic interaction with the commonly used drugs rifampicin and nifedipine. Interaction of Diabecon with rifampicin: The pharmacokinetic interaction of rifampicin and Diabecon (D-400) was studied in animal models as well as in healthy human volunteers. Twelve rabbits were divided into two groups of six each. Animals in group I were treated with rifampicin (100 mg/kg body weight, p.o.) and group II with rifampicin (100 mg/kg body weight, p.o.) and Diabecon (D-400) (1 g/kg body weight, p.o.) for a period of 8 days. Rifampicin levels in plasma were estimated on day 1 and day 8 at 2, 4, 6 and 8 h after drug administration. On the basis of these findings, a clinical study in 9 healthy human volunteers aged 25-35 years and weighing 50-75 kg was initiated. They were given 450 mg of rifampicin once only on day 1 and from the second day onwards were given 2 tablets of Diabecon (D-400) twice daily for 7 days. On day 9, another dose of rifampicin (450 mg) was given along with 2 tablets of Diabecon (D-400). Blood samples were collected at 2, 4, 6 and 8 h after drug administration on day 1 and day 9 to estimate the rifampicin levels in plasma. Interaction of Diabecon with nifedipine: In another study, 12 rabbits were divided into two groups of 6 each. Group I animals were treated with nifedipine (2.5 mg/kg body weight, p.o.) and Group II animals were treated with nifedipine (2.5 mg/kg body weight, p.o.) and Diabecon (D-400) (1 g/kg body weight, p.o.) for a period of 8 days. On day 1 and day 8, blood samples were collected at 1, 2, 4 and 6 h after drug administration and plasma nifedipine levels were estimated. The results of these three studies revealed that Diabecon (D-400) did not alter the pharmacokinetic profiles of rifampicin and nifedipine.

The effect of ranitidine pretreatment on the pharmacokinetics of omeprazole was investigated in 14 male human volunteers. Omeprazole (40 mg, gastroresistant pellets) was administered to the volunteers in a two-treatment study design, either alone or after 5 days pretreatment with b.i.d. doses of 150 mg ranitidine. Plasma concentrations of omeprazole were determined over a 24-hour period following drug administration, by a validated RP-HPLC method. Pharmacokinetic parameters were calculated with compartmental and non-compartmental analysis, using the computer program Kinetica (Inna Phase). In the two periods of treatments, the mean peak plasma concentrations Cmax were 730.8 ng/ml for omeprazole alone and 802.1 ng/ml for omeprazole co-administered with ranitidine (not significant). The time taken to reach the peak, Tmax, was 1.29 h and 1.42 h, respectively (not significant). The areas under the curve (AUC0-10) were 1,453.3 ng.h/ml and 1,736.8 ng.h/ml for the two periods of treatment; thus a greater AUC was obtained after pretreatment with multiple doses of ranitidine. Our data show that the pharmacokinetics of omeprazole might be inhibited by pretreatment with ranitidine; however, the clinical relevance of this interaction still has to be confirmed.

Five healthy volunteers received a single 0.5-mg dose of triazolam on two occasions: once with 100 to 200 ml of water, and on a second trial with 60 ml of commercial vodka mixed with 60 ml of water. There were no significant differences between control and ethanol-coadministration trials in peak serum triazolam level (5.4 vs. 5.4 ng/ml), time of peak level (1.5 vs. 1.6 hours), elimination half-life (2.8 vs. 2.6 hours), or apparent oral clearance (6.6 vs. 7.9 ml/min/kg). The potential pharmacodynamic interaction of triazolam and ethanol is more important than the minimal pharmacokinetic interaction.

Intravenous imipramine and desipramine were administered to two detoxified alcoholics before and during disulfiram treatment. Tricyclic pharmacokinetic parameters, determined from plasma samples over 48 hours, indicated decreased total body clearance, increased elimination half-life, and higher peak plasma levels during disulfiram treatment.