Pharmacokinetics of aditoprim in goats using a radioassay

A simple, highly sensitive radioassay was developed for the activity of a newly discovered inhibitor of dihydrofolate reductase (DHFR), aditoprim. The procedure is based on the inhibition of binding of [³H]-methotrexate ([³H]MTX) with bacterial dihydrofolate reductase by the antifolate, aditoprim. The analytic sensitivity using this binding inhibition method was less than 5 ng in plasma. The procedure developed requires no extraction of the drug from the plasma. The variation of simultaneous duplicate determinations was 6·3 per cent, whereas the variability of plasma samples assayed on different days was less than 11 per cent. The assay developed was applied to study the pharmacokinetics of aditoprim in the goat. In comparison with trimethoprim (TMP), the new inhibitor of DHFR, aditoprim, had a longer half-life and a larger volume of distribution, suggesting enhanced and prolonged antibacterial activity of aditoprim over TMP.     

Influence of Age on Half-life of Trimethoprim and Sulphadoxine in Goats

Abstract The half-life of trimethoprim is about 40 min. in adult goats and 4–5 times longer in newborn kids. During the neonatal period the half-life decreases to the level found in adult goats when the body weight is about 10 kg corresponding to an age of 40–50 days. The half-life of sulphadoxine is about 12 hours in adult goats and there is a tendency towards a longer half-life in newborn and young kids, but the difference is not significant. The apparent volume of distribution for both trimethoprim and sulphadoxine is higher in newborn kids than in adult animals. The apparent volume of distribution for trimethoprim decreases during the neonatal period while that of sulphadoxine is nearly constant until an age of 16 weeks.     

The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects

AIMS: Rosiglitazone, a thiazolidinedione antidiabetic medication used in the treatment of Type 2 diabetes mellitus, is predominantly metabolized by the cytochrome P450 (CYP) enzyme CYP2C8. The anti-infective drug trimethoprim has been shown in vitro to be a selective inhibitor of CYP2C8. The purpose of this study was to evaluate the effect of trimethoprim on the CYP2C8 mediated metabolism of rosiglitazone in vivo and in vitro. METHODS: The effect of trimethoprim on the metabolism of rosiglitazone in vitro was assessed in pooled human liver microsomes. The effect in vivo was determined by evaluating rosiglitazone pharmacokinetics in the presence and absence of trimethoprim. Eight healthy subjects (four men and four women) completed a randomized, cross-over study. Subjects received single dose rosiglitazone (8 mg) in the presence and absence of trimethoprim 200 mg given twice daily for 5 days. RESULTS: Trimethoprim inhibited rosiglitazone metabolism both in vitro and in vivo. Inhibition of rosiglitazone para-hydroxylation by trimethoprim in vitro was found to be competitive with apparent K(i) and IC(50) values of 29 microm and 54.5 microm, respectively. In the presence of trimethoprim, rosiglitazone plasma AUC was increased by 31% (P = 0.01) from 2774 +/- 645 microg l(-1) h to 3643 +/- 1051 microg l(-1) h (95% confidence interval (CI) for difference 189, 1549), and half-life was increased by 27% (P = 0.006) from 3.3 +/- 0.5 to 4.2 +/- 0.8 h (95% CI for difference 0.36, 1.5). Trimethoprim reduced the para-O-sulphate rosiglitazone/rosiglitazone and the N-desmethylrosiglitazone/rosiglitazone AUC(0-24) ratios by 22% and 38%, respectively. CONCLUSIONS: These results indicate that trimethoprim is a competitive inhibitor of CYP2C8-mediated rosiglitazone metabolism in vitro and that trimethoprim administration increases plasma rosiglitazone concentrations in healthy subjects.     

Pharmacokinetic analysis of the level of sulfonamide-trimethoprim combination in calves

Pharmacokinetic parameters which describe biological availability (AUC, Cmax, tmax) and elimination (kel, t 1/2) of sulfonamides and trimethoprim were determined in calves. Pharmacokinetic analysis was based upon "one compartment model". The average +/- SD half-life in plasma was for sulfametoxazole 12.8 +/- 0.32 h, for sulfamerazine 17.0 +/- 0.75 h and for sulfachloropyridazine 13.1 +/- 0.86 h. The average half-life of trimethoprim in plasma was 11.3 +/- 0.56 h. In fasted calves the concentrations of sulfachloropyridazine and trimethoprim in plasma were higher as compared with fed group.     

Effect of severe protein-calorie malnutrition on the penetration kinetics of trimethoprim and sulfamethoxazole to the deep tissues of Wistar rats

This study shows the effect that severe malnourishment has on the kinetics of antibiotic penetration in tissues. A total of 104 male Wistar rats, 21 days old, were randomly divided into eight groups. Five groups of experimental rats were severely malnourished (SM) and three further groups were considered well-nourished control groups (WN). A single dose of trimethoprim-sulfamethoxazole (TMP-SMX) was administered intraperitoneally. Blood samples were taken by heart puncture and five organs were extracted 0-24 h after the administration of the drug. HPLC was used to assess the amount of trimethoprim and sulfamethoxazole in fluids. The elimination half-life for trimethoprim from plasma was longer in SM rats with a median of 3.15 h; in WN rats, it was 0.390 h. Clearance was slower in SM rats: 646.72 mL microg(-1) h(-1) vs 3036.38 mL microg(-1) h(-1) in WN rats (P < 0.05). Tissue penetration was much higher for trimethoprim, with penetration indexes of 0.80-5.66 in WN rats, compared with 0.35-2.14 in SM rats. In the case of sulfamethoxazole, penetration indexes were 0.029-1.13 for WN and 0.075-0.657 for SM rats. Similarly, the penetration ratio to muscle and heart tissue was lower in SM rats. However, penetration to kidney, lung, liver and spleen was greater in SM rats. It is evident that severe SM decreases the capacity of trimethoprim more importantly than sulfamethoxazole biotransformation.     

Pharmacokinetic studies of mitoxantrone and one of its metabolites in serum and urine in patients with advanced breast cancer

Objective: Mitoxantrone (MTO) was administered to patients with advanced breast cancer either as free MTO (f-MTO) or liposomal MTO (l-MTO). The intra- and interindividual variations in serum pharmacokinetics of MTO were analysed. In addition, the excretion of MTO and its metabolite mitoxantrone dicarboxylic acid (MTOD) in urine was determined. Methods: The concentration of MTO was measured by high-performance liquid chromatography in serum over a period of 24 h and the amount of MTO and the metabolite MTOD excreted in urine over 18 h was determined. Pharmacokinetic parameters of f-MTO and l-MTO were calculated. Results: l-MTO had a significantly longer half-life of distribution in the deep (third) compartment and thus a larger area under the curve (AUC) than f-MTO. No difference was found with respect to distribution in the peripheral (second) compartment. The kinetics of MTO in serum did not significantly differ between patients. In four patients repeated pharmacokinetic analyses gave superimposable results. Thus, there was no enzyme induction during therapy. By contrast, two patients with oedema had a much longer mean residence time (MRT) and AUC for MTO in serum. Despite the altered pharmacokinetics of f-MTD and l-MTO, no toxic adverse effects occurred in these two patients. Conclusions: f-MTO and l-MTO exhibited different distribution patterns in the deep compartment with a significantly increased half-life for l-MTO. There is no need to monitor MTO for treatment of breast cancer patients with f-MTO. In patients with oedema, the MRT of MTO is prolonged. The clinical relevance of this observation is as yet unclear. Received: 14 April 1997 / Accepted in revised form: 11 December 1997     

Trimethoprim–metformin interaction and its genetic modulation by OCT2 and MATE1 transporters

Aims

Metformin pharmacokinetics depends on the presence and activity of membrane-bound drug transporters and may be affected by transport inhibitors. The aim of this study was to investigate the effects of trimethoprim on metformin pharmacokinetics and genetic modulation by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1) polymorphisms.

Methods

Twenty-four healthy volunteers received metformin 500 mg three times daily for 10 days and trimethoprim 200 mg twice daily from day 5 to 10. Effects of trimethoprim on steady-state metformin pharmacokinetics were analysed.

Results

In the population as a whole, trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l h⁻¹ and renal metformin clearance from 31 to 21 l h⁻¹, and prolonged half-life from 2.7 to 3.6 h (all P < 0.01). This resulted in an increase in the maximal plasma concentration by 38% and in the area under the plasma concentration–time curve by 37%. In volunteers polymorphic for both OCT2 and MATE1, trimethoprim had no relevant inhibitory effects on metformin kinetics. Trimethoprim was associated with a decrease in creatinine clearance from 133 to 106 ml min⁻¹ (P < 0.01) and an increase in plasma lactate from 0.94 to 1.2 mmol l⁻¹ (P = 0.016).

Conclusions

The extent of inhibition by trimethoprim was moderate, but might be clinically relevant in patients with borderline renal function or high-dose metformin.     

Inhibition of dapsone-induced methaemoglobinaemia by cimetidine in the presence of trimethoprim in the rat.

Administration of dapsone in combination with trimethoprim and cimetidine to male rats resulted in a marked decrease (P less than 0.05) in measured methaemoglobin levels (46.2 +/- 24% Met Hb h) compared with administration of dapsone alone (124.5 +/- 24.4% Met Hb h). The elimination half-life of dapsone (814 +/- 351 min) was more than doubled in the presence of trimethoprim and cimetidine compared with control (355 +/- 160 min, P less than 0.05). However, there were no significant differences in AUC and clearance when dapsone was administered in combination with trimethoprim and cimetidine compared with dapsone alone. Co-administration of trimethoprim with dapsone in the absence of cimetidine did not affect either methaemoglobin formation, AUCs, half-lives, or clearance values of dapsone compared with control. There was a threefold increase in the AUC of trimethoprim (6296 +/- 2249 micrograms min mL-1) in the presence of dapsone compared with trimethoprim alone (2122 +/- 552 micrograms min mL-1). There was also a corresponding decrease in the clearance of trimethoprim in the presence of dapsone compared with control (19.1 +/- 6.9 vs 60.8 +/- 21.0 mL min-1). However, there was no change in the elimination half-life of trimethoprim between the two experimental groups (273 +/- 120 vs 292 +/- 54 min). The AUC of trimethoprim increased more than threefold in the presence of cimetidine (7100 +/- 1501 micrograms min mL-1) compared with trimethoprim alone (2122 +/- 552 micrograms min mL-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of Streptococcus pneumoniae and Influenza A Virus on Middle Ear Antimicrobial Pharmacokinetics in Experimental Otitis Media

Antimicrobial treatment failures in children with acute otitis media and concomitant viral respiratory tract infection prompted us to study the effects of influenza A virus infection on middle ear antimicrobial drug penetration. Using a chinchilla model of Streptococcus pneumoniae we compared middle ear elimination rates in 4 groups of chinchillas: (1) control, (2) influenza A virus inoculation alone intranasally, (3) both influenza A and S. pneumoniae inoculation directly into the middle ear, and (4) S. pneumoniae inoculation alone into the middle ear. After infection was established, a solution containing amoxicillin, sulfamethoxazole, and trimethoprim was instilled into the middle ear and removed 4 hours later. The rate constant of elimination and half-life were calculated from measured drug concentrations initially and at 4 hours. S. pneumoniae infection alone significantly shortened the middle ear elimination half-life compared with the control group: amoxicillin, 2.65 ± 0.73 vs. 6.63 ± 2.55 hr; sulfamethoxazole, 1.75 ± 0.28 vs. 2.74 ± 0.6 hr; and trimethoprim, 1.06 ± 0.14 vs. 1.56 ± 0.34 hr (n = 16 ears, p values all <0.01). The combined influenza virus and S. pneumoniae infection significantly lengthened the half-life compared with the S. pneumoniae infection alone: amoxicillin, 5.65 ± 6.44 vs. 2.65 ± 0.73 hr; sulfamethoxazole, 2.5 ± 0.85 vs. 1.75 ± 0.28 hr; and trimethoprim, 1.26 ± 0.42 vs. 1.06 ± 0.14 hr (n = 16 ears, p values all <0.01). Influenza virus produced the longest half-lives for all 3 antimicrobials: amoxicillin 25.52 ± 14.96 hr; sulfamethoxazole, 5.46 ± 0.87 hr; and trimethoprim, 2.57 ± 0.75 hr. These effects demonstrate that influenza and S. pneumoniae infections alone and together affect middle ear antimicrobial penetration. The decreased penetration of antimicrobials that occurred with the combined viral and bacterial infection vs. the bacteria alone supports the clinical observation that patients with infections caused by both organisms may have decreased middle ear antimicrobial concentrations, producing treatment failures.     

The pharmacokinetics of cefixime in the fasted and fed state

Summary Twenty healthy adult volunteers received single 400 mg oral doses of cefixime in an open, randomized, crossover study, administered twice in the fasted state and twice with a standard breakfast. The study design allowed both an evaluation of a potential food effect and also an analysis of both intrasubject and intersubject variability in the fasted and fed state.There was a small but significantly longer (1 h) time to peak concentration when the drug was given with food. Peak serum concentrations, area under the curve, and 24 h urinary recovery values were unchanged in the fed and fasted states. The terminal elimination half-life of the drug given after a meal (3.6 h) was slightly longer than that observed after dosing in the fasting condition (3.5 h).The intrasubject and intersubject variabilities were less than 12% and 33% respectively, for both area under the curve and 24 h urinary recovery, and were virtually the same for the fasted and fed occasions. Therefore, the drug may be administered with or without food.     

Lignocaine and indocyanine green kinetics in patients following myocardial infarction.

1. Blood clearances of lignocaine and indocyanine green together with indocyanine green half-lives were measured in 17 post-myocardial infarct patients (one patient was studied twice) between 8 h and 36 h after starting intravenous lignocaine infusions for the treatment of cardiac arrhythmias. 2. Mean +/- s.d. values of lignocaine clearance (ml min-1 kg-1) were higher in patients without heart failure (11.8 +/- 2.6, n = 9) than in those with heart failure (7.2 +/- 1.9, n = 9) (P < 0002). 3. Clearances of lignocaine and indocyanine green were not correlated but lignocaine clearance was directly related to the reciprocal of indocyanine green half-life (rs = 0.67, P < 0.01). 4. In eight patients who received both lignocaine and indocyanine green and in a further five patients received only lignocaine and whose lignocaine infusions lasted 24h or more, a 25% rise in lignocaine concentrations was observed between 8-12h and 24-28h. 5. The mean +/- s.d. post-infusion terminal half-life of lignocaine in four patients whose lignocaine infusions lasted 30h or longer was 7.2 +/- 2.1 h. 6. Heart failure was associated with greater changes in lignocaine kinetics than in indocyanine green kinetics. 72% of the variance between observed and predicted lignocaine clearances could be accounted for by multiple linear regression analysis incorporating indocyanine green half-life and the presence or absence of heart failure. Indocyanine green half-life contributed only 17% of the variance indicating that by itself it is of limited value in predicting lignocaine requirements. 7. Lignocaine kinetics during and after prolonged intravenous infusion were not predicted by data obtained after intravenous bolus injection. 8. A lowering of lignocaine dosage may be clinically desirable in the presence of heart failure and if an infusion lasts longer than 24 h.     

Effects of drugs on aminophylline elimination in rats

Effects of phenobarbital, phenytoin, carbamazepine, cimetidine, erythromycin, combination of sulfamethoxazole + trimethoprim (5:1), and rifampicin (rifampin) on the elimination of aminophylline were examined in female rats. Aminophylline was administered i.p. in a dose of 13.33 mg/kg. Blood samples were collected 0.5, 2, 4 and 7 h after the administration of the injection; one measurement was performed from one blood sample. Plasma aminophylline levels were measured by a modified HPLC method. The elimination half-life of the untreated control group (n = 27) was 4.62 h. The pretreatments with drugs examined were carried out by a gastric tube. The half-life of aminophylline after phenobarbital (10 mg/kg, 7 days, n = 29) was 2.09 h; after phenytoin (10 mg/kg, 7 days, n = 29), 2.47 h; after carbamazepine (400 mg/d, 7 days, n = 25), 2.19 h; after cimetidine (in cimetidine-treated group the blood samples were collected 0.5, 4 and 7 h after the aminophylline injection) (40 mg/kg, 7 days, n = 13), 1.77 h; after erythromycin (800 mg/d, 7 days, n = 28), 2.51 h; after the combination of sulfamethoxazole + trimethoprim in ratio of 5:1 (50 mg/kg, 7 days, n = 23), 2.85 h; and after rifampicin (300 mg/kg, 21 days, n = 23), 2.74 h. Sulfamethoxazole presumably interfered with the HPLC examination of aminophylline.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of phenylethylmalonamide (PEMA) in elderly men

Summary The pharmacokinetics of phenylethylmalonamide (PEMA) were studied in 6 elderly men after oral administration of a single 400 mg dose.Peak PEMA serum levels were obtained within 4 h of intake, half-life values ranged from 30.7–57.9 h in these elderly men.The elimination half-life was twice as long when compared to a study previously performed in young volunteers.     

Pharmacokinetics of intravenous and oral isosorbide-5-mononitrate

Summary The pharmacokinetics of isosorbide-5-mononitrate (IS-5-MN) has been studied in two groups of healthy volunteers after oral (n=20) and intravenous (n=11) administration of 20 mg, which had previously been proved to be as effective as 20 mg sustained-release isosorbide dinitrate (ISDN). IS-5-MN in serum was measured by gas chromatography using capillary columns. The kinetic calculations were carried out with a newly developed model, which assumes a virtual volume of distribution dependent on time. IS-5-MN is rapidly (invasion half-life 4.1 min) and completely absorbed from the gastro-intestinal tract without any first pass metabolism. The maximum concentration of 480 µg/l was reached 1.2 h after oral administration of 20 mg. The substance was distributed throughout the total body water (distribution coefficient: 0.62), and was eliminated with a terminal t_1/2 of 4.1 and 4.6 h after oral and intravenous administration, respectively. Total body clearance was 115 ml/min. Thus, IS-5-MN is unlike ISDN with respect to the absence of first-pass metabolism and an 8-times longer half-life. The consequences for therapy are discussed.     

Pharmacokinetics of furosemide in patients with hepatic cirrhosis

Summary The pharmacokinetics of furosemide was studied in 7 patients with diagnosed liver cirrhosis and in 7 healthy subjects. Furosemide in plasma and ascitic fluid was analyzed spectrofluorometrically. After a single intravenous dose, the cirrhotic patients showed lower initial plasma concentrations of furosemide because of the larger volume of distribution. The mean half-life in cirrhotic patients was significantly greater than in healthy volunteers. The longer half-life was associated with a reduction in the serum clearance of furosemide. Ascitic fluid volume in the patients ranged from 4.6 to 7.71. There was no significant amount of furosemide in the fluid. The diuretic interchange between this fluid and plasma was slow, as peak concentrations ranged from 0.3 to 0.5 µg/ml within 3 to 5 h after bolus administration of furosemide. Diuresis and urinary sodium excretion, 5 h after furosemide injection, were similar in both groups; larger potassium excretion was found in the cirrhotic patients.     

Time course of central nervous dopamine-D2 and 5-HT2 receptor blockade and plasma drug concentrations after discontinuation of quetiapine (Seroquel®) in patients with schizophrenia

Quetiapine (Seroquel) is a novel antipsychotic with an atypical profile in animal models and a relatively short plasma half-life of 2.5–5 h. In the present study, we used PET to compare the time course of blockade of dopamine D₂ and serotonin 5HT₂ receptors of quetiapine using C¹¹-raclopride and C¹¹-N-methyl-spiperone as ligands, parallel to monitoring plasma drug concentrations. It was an open study in 11 schizophrenic men using a fixed dose of 450 mg quetiapine. Eight men completed the 29 days treatment, followed by four PET scans performed over a 26-h period after withdrawal of the compound. Quetiapine was shown to bind to dopamine D₂ receptors in striatum and 2 h (t_max) after the last dose, 44% receptor occupancy was calculated. After 26 h it had dropped to the same level as was found in untreated healthy volunteers. Serotonin 5HT₂ receptor blockade in the frontal cortex was 72% after 2 h, which declined to 50% after 26 h. The terminal plasma half-life of quetiapine was 5.3 h. Clinically, our eight patients had good antipsychotic effect without any extrapyramidal side-effects. Our data shows that quetiapine has a relatively low affinity for dopamine D₂ receptors, with an occupancy half-life (10 h), which was about twice as long as that for plasma. A more prolonged blockade of the serotonin 5HT₂ receptors was found in the frontal cortex, with receptor occupancy half-life of 27 h. Compared to clozapine, as demonstrated in other studies, quetiapine has much the same ratio of D₂/5HT₂ occupancy. This could suggest that the combination of D₂/5HT₂ receptor blockade contributes to the antipsychotic effect and a low incidence of EPS seen with quetiapine in comparative phase three trials. Our results also confirm the clinical data that quetiapine can be administered twice daily. Received: 13 December 1996/Final version: 13 June 1997     

Comparative drug elimination in man — Diphenylhydantoin and amobarbital

Summary The concentration of 5,5-diphenylhydantoin (DPH) in serum was determined at selected time intervals in seven healthy male volunteers starting 10 h after an oral dose of 400 mg sodium DPH was given. The data were analyzed according to a one-compartment model assuming first-order kinetics. The mean serum half-life was 19.28 h±5.87 (SD). A positive correlation coefficient (r=0.84, p<0.05) was found between the serum DPH half-life and the serum amobarbital half-life in the seven subjects. The urinary levels of free plus conjugated 5-(p-hydroxyphenyl)-5-phenylhydantoin were determined for 12 h periods over a minimum of two days following the 400 mg oral dose of sodium DPH. Subjects with a short DPH half-life tended to excrete in urine a greater amount ofp-HPPH as compared to subjects with a long DPH half-life. In the case of one subject, the urinary excretion ofp-HPPH plateaued five days after DPH administration and the apparent elimination half-life determined from thep-HPPH urinary excretion data was 19.16 h as compared to the value of 19.53 h calculated from the DPH serum levels.     

Phenazone (antipyrine) metabolism and distribution in young and elderly adults

1. The plasma half-life and apparent volume of distribution of phenazone (antipyrine) was studied in twenty-six normal adults (20–40 years of age) and twenty-six geriatric patients. 2. A wide range of values for plasma half-life was recorded in both groups (young 7·7–19·9 h, elderly 9·5–30·1 h) but the mean plasma half-life for the geriatric group (16·8 h; s.e.m. = 5·9) was significantly longer (P < 0·01) than the normal adult group (12·5 h; s.e.m. = 3·2). 3. No difference in plasma half-life was noted between sexes in either the geriatric or control groups. 4. Doubling the dose of phenazone from 10 to 20 mg/kg made no difference to the plasma half-life in a subgroup of the geriatric patients. 5. The volume of distribution of phenazone, representing total body water, was 0·59–0·63 l/kg in all groups except the elderly females, in whom it was 0·48 l/kg. This latter group showed a correspondingly higher plasma concentration extrapolated to time zero. 6. The difference in plasma half-life phenazone between normal adult and elderly groups is statistically significant, but the wide range of values in each group makes the biological significance less clear. Alteration of drug distribution with resultant higher plasma or tissue concentrations may contribute to adverse drug effects, particularly in the elderly female.     

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.     

Cotrimoxazole as an inhibitor of oxidative drug metabolism: effects of trimethoprim and sulphamethoxazole separately and combined on tolbutamide disposition.

The effect of separate pretreatments with cotrimoxazole, sulphamethoxazole and trimethoprim on the disposition of tolbutamide was studied in seven healthy males. Tolbutamide 500 mg intravenously was administered on four separate occasions--as a control without pretreatment and on the seventh day of separate twice daily administration of cotrimoxazole (sulphamethoxazole 800 mg plus trimethoprim 160 mg) (ST phase), sulphamethoxazole 1 g (S phase) and trimethoprim 150 mg (T phase). Tolbutamide total and unbound plasma clearance (CL) were reduced following each of the individual pretreatments compared to the control phase (P less than 0.001). For unbound CL the reductions were 14% in the S and T phases and 25% in ST phase. Tolbutamide elimination half-life was prolonged following each pretreatment (P less than 0.001) by 20% in the S phase, 19% in the T phase and 30% in the ST phase. Tolbutamide total steady-state volume of distribution (VSS) was increased by 10% in the S and ST phases (P less than 0.01), the increase being accounted for by an increase in tolbutamide unbound fraction. There was no change in tolbutamide unbound VSS following any of the pretreatments. These results are consistent with inhibition of tolbutamide oxidation by cotrimoxazole, an additive effect of the two components sulphamethoxazole and trimethoprim. Sulphamethoxazole also reduces tolbutamide plasma protein binding.