Pharmacokinetics of Oral Co-Trimazine and the Penetration of Its Components Sulfadiazine and Trimethoprim into Peripheral Human Lymph

Bergan, Tom; Engeset, A; Olszewski, Waldemar L.

doi:10.1159/000238418

Cited by 10 publications

(5 citation statements)

References 14 publications

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“…Relevant is that one tablet of co-trimazine once daily [2,8,17] has been thera peutically successful. The duration of SDZ and TMP in peripheral human lymph [4] supports the observation that dosage once daily is sufficient also in the elderly for the treatment of urinary tract infections.…”

Section: Discussionsupporting

confidence: 71%

“…The difference was not as marked, but there was no significant distinction be tween SDZ or TMP. In the second part of the study, the rise of the concentrations of both SDZ and TMP were higher than ob served in healthy subjects [4], This differ ence is undoubtedly caused by the lower renal function of elderly subjects even though the serum creatinine level may be normal. Prolonged elimination of TMP and sulphonamides may be expected in the elderly.…”

Section: Discussionmentioning

confidence: 67%

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Pharmacokinetics of Co-Trimazine (Sulphadiazine plus Trimethoprim) in Geriatric Patients

Bergan

Allgulander²,

Fellner

1986

Chemotherapy

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The study was aimed at analyzing the pharmacokinetics of sulphadiazine (SDZ) and trimethoprim (TMP) in geriatric patients and was carried out in two stages. The first stage compared 11 geriatric patients (68–89 years old) and 9 healthy volunteers (21–34 years old). Serum concentration and urine elimination were determined on day 4 after 12-hourly administration of 1 tablet of co-trimazine containing 410 mg sulphadiazine (SDZ) plus 90 mg trimethoprim (TMP). The mean serum concentrations of SDZ were significantly higher in the older subjects than in the volunteers after 1, 8 and 12 h (p < 0.05, 0.01, 0.01), but were not differentiable after 2 or 4 h. For TMP, the serum levels were higher (p < 0.05) in the patients only after 8 h. The amounts collected in urine were higher in the normal volunteers for SDZ during the intervals 0–2 h (p < 0.05), 2–4 h (p < 0.01), and 4–8 h (p < 0.01), but not for 8–12 h. The 12-hour recovery was 69% SDZ + acetyl-SDZ recovered in the patients compared to 66.0% in the volunteers. Indistinguishable amounts of TMP were recovered during each interval in the two groups of subjects, 59.2% in the patients compared to 70.0% in the volunteers. The second stage of the study comprised 9 geriatric patients of mean age 83.6 years and creatinine clearance 59.2 ml/min who were followed for 11 days. A steady increase in serum levels was observed. The mean peak serum concentration for SDZ was 16.7 ± 4.2 mg/l after the first dose and 44.7 ± 11.3 mg/l on day 10. For acetyl-SDZ, the respective concentrations were 2.1 ± 0.9 and 7.1 ± 3.1 mg/l. TMP rose from 0.79 ± 0.19 mg/l on the first day to 2.8 ± 1.3 mg/l on day 10. Parallel increases in urine elimination of SDZ, acetyl-SDZ and TMP were observed over the 11 days. After the first dose, the 12-hour urine elimination of SDZ corresponded to 16.2% of the dose, that of acetyl-SDZ to 7.5% and of TMP 21.5%. After the final dose, the respective 48-hour values were 103.2, 51.2 and 115%. The t_½ was 16.2 ± 5.6 h for SDZ, 25.5 ± 12.3 h for acetyl-SDZ, and 14.0 ± 6.0 h for TMP.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 67%

Pharmacokinetics of Co-Trimazine (Sulphadiazine plus Trimethoprim) in Geriatric Patients

Bergan

Allgulander²,

Fellner

1986

Chemotherapy

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“…In a study with co-trimazine, we have monitored the concentrations of sulphadiazine and trimethoprim in human peripheral lymph collected from subcutaneous collective lymph vessels by catheterisation as described by Engeset et al (1972). Following doses of 1.0g co-trimazine, peak concentrations in the lymph were present at 3 to 4 hours (Bergan et al 1986). At steady-state, the peaks were 27.7 ± 4.3 mg/L for sulphadiazine and 1.6 ± 0.68 mg/L for trimethoprim, with the simultaneous serum concentrations being 31.7 ± 5.8 mg/L and 2.3 ± 0.51 mg/L, respectively ( fig.…”

Section: Distributionmentioning

confidence: 97%

“…Area under the plasma concentration·time curve (AUC(O.24») and total amount recovered during 24 hours (Ae24) of sulphadiazine (SOZ) and trimethoprim (TMP) following a single dose of 1 .Og co-trimazine given in either 1 or 2 tablets in a randomised crossover fashion to 9 healthy volunteers (24 to (Bergan et al 1986). …”

Section: Eliminationmentioning

confidence: 99%

Clinical Pharmacokinetics of Co-Trimazine

Bergan¹,

Örtengren²,

Westerlund³

1986

Clinical Pharmacokinetics

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The clinical pharmacokinetics of co-trimazine (trimethoprim plus sulphadiazine) are reviewed and compared with those of co-trimoxazole (trimethoprim plus sulphamethoxazole). Both combination drugs have similar serum half-life values in persons with normal renal function (half-life of 8 to 12 hours), but the sulphamethoxazole metabolites are retained more than trimethoprim in reduced renal function. Sulphadiazine is less metabolised and the total sulphonamide load of therapeutic doses of co-trimazine is therefore less than for co-trimoxazole. Both co-trimazine and co-trimoxazole have high bioavailability. A suspension of co-trimazine gives serum concentrations comparable with those of tablets. The extravascular penetration of the co-trimazine components is reflected by the total area under the lymph concentration curve in comparison with serum. This measure shows a penetration into peripheral human lymph of 68% for sulphadiazine and 59% for trimethoprim. The proportions eliminated in urine are about 55% for sulphadiazine, 30% for its acetylated metabolite and 75% for trimethoprim. In comparison, for co-trimoxazole, the proportion of sulphamethoxazole eliminated in urine is 15%, that of the acetylated derivative 47%, and that of trimethoprim is also 75%. Urine concentrations of both combinations have similar bioactivity against urinary pathogens after 500 mg of co-trimazine and 960 mg of co-trimoxazole.

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“…Penetration of co-trimoxazole into breast milk is similar to that into saliva (Arnauld et al 1972), and into aqueous humour is 20% and 30%, respectively, of serum concentrations of trimethoprim and sulphamethoxazole (Salmon et al 1975). Penetration into lymph tissue is 59 and 68% for trimethoprim and sulphadiazine, respectively (Bergan et al 1986b).…”

Section: Distributionmentioning

confidence: 98%

Clinical Pharmacokinetics of Enzyme Inhibitors in Antimicrobial Chemotherapy

Watson

Stewart

Platt

1988

Clinical Pharmacokinetics

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The effectiveness of some antimicrobial agents can be enhanced by using them in combination; such combinations are termed synergistic. Where one compound potentiates the effect of a second drug they may be coformulated. Inhibition of the bacterial degradation of an active antimicrobial is the basis of clavulanate and sulbactam-potentiated penicillin combinations, and inhibition of degradative pathways in the host is the rationale behind imipenem/cilastatin therapy. Trimethoprim/sulphonamide combinations depend on the maintenance of an effective ratio for synergistic action. In order to achieve potentiation the coformulated drugs should have similar pharmacokinetics. Trimethoprim was originally matched with sulphamethoxazole, since these two drugs have similar elimination half-lives, but the significantly poorer penetration of sulphonamides, their greater non-renal clearance, the emergence of resistance, and the adverse reactions attributable to them argue against the rationale that underlies their coformulation. Time-dependent inhibition of bacterial beta-lactamases by clavulanic acid and sulbactam has extended the use of penicillins which are highly susceptible to beta-lactamase inactivation. The beta-lactamase inhibitors must penetrate to the same extent as the penicillin used with them, and be present long enough to effect inhibition; thus, rapid penetration, similar or slower elimination and equivalent volume of distribution are necessary. These requirements are met for amoxycillin/clavulanic acid, ticarcillin/clavulanic acid and ampicillin/sulbactam combinations. Clavulanic acid is absorbed orally and is given with amoxycillin. However, since sulbactam is labile by this route, the combination of sulbactam with ampicillin to form the prodrug sultamicillin has been necessary to enable an oral form to be developed. Imipenem is metabolised by renal brush-border dehydropeptidases, and may cause proximal tubular necrosis. Cilastatin was designed to inhibit this metabolism, which it effectively does, thereby both potentiating the effect of imipenem and avoiding toxicity. Appropriate matching of the kinetics of coformulated drugs is intended to maximise potentiation and minimise the risk of emergent resistance. The kinetics of the above combinations are discussed in the light of these requirements and the effects of age and disease.

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Pharmacokinetics of Oral Co-Trimazine and the Penetration of Its Components Sulfadiazine and Trimethoprim into Peripheral Human Lymph

Cited by 10 publications

References 14 publications

Pharmacokinetics of Co-Trimazine (Sulphadiazine plus Trimethoprim) in Geriatric Patients

Pharmacokinetics of Co-Trimazine (Sulphadiazine plus Trimethoprim) in Geriatric Patients

Clinical Pharmacokinetics of Co-Trimazine

Clinical Pharmacokinetics of Enzyme Inhibitors in Antimicrobial Chemotherapy

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