Physicochemical Properties of Amphoteric β-Lactam Antibiotics I: Stability, Solubility, and Dissolution Behavior of Amino Penicillins as a Function of pH

Tsuji, Akira; Nakashima, Emi; Hamano, Shoichiro; Yamana, Tsukinaka

doi:10.1002/jps.2600670810

Cited by 129 publications

(72 citation statements)

References 26 publications

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“…The solubility of ampicillin and amoxycillin in human urine at 37°C was higher than that previously described in water (Tsuji et al, 1978). Our results for urine also indicate Ushaped pH-solubility curves, with minimum solubility at the pH near the isoelectric point.…”

Section: Discussionsupporting

confidence: 54%

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Renal excretion of intravenously infused amoxycillin and ampicillin.

Sjövall¹,

Westerlund²,

Alván³

1985

Brit J Clinical Pharma

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1 The aim of this study was to determine whether concentration-dependent renal clearance of ampicillin and amoxycillin occurs. The drugs were given as single 20 min i.v. infusions in doses ranging from 1.9 to 2.8 g to nine healthy volunteers using a cross-over design. 2 Plasma and urinary concentrations were determined by a selective liquid chromatographic method using frequent sampling up to 10 and 30 h respectively after termination of the infusion. The renal clearance of the drugs was independent of the plasma concentration. The mean (s.d.) renal clearances of ampicillin and amoxycillin were 167 (24) and 157 (20) ml min-' 1.73 m-2 respectively. The net secretion was about 50% of the total renal clearance of both drugs. 3 The plasma concentration and urinary excretion rate versus time curves indicated a polyexponential decline, which could be described by both a biexponential and a triexponential equation. The former proved to be more reliable, especially in the calculation of micro rate constants. There was a tendency to more sustained plasma concentrations after amoxycillin, also illustrated by a significantly lower mean (s.d.) plasma clearance of this drug, viz. 185 (30) ml min-1 1.73 m-2, as compared to ampicillin, 210 (24) ml min-' 1.73 m-2 (P < 0.04). 4 There were no major differences in the disposition rate constants and the distribution volumes of ampicillin and amoxycillin. The mean (s.d.) plasma half-life was 1.7 (0.3) h for both drugs. The urinary excretion rate indicated a slower terminal disposition rate however, with ampicillin and amoxycillin half-lives of 3.4 (2.0) and 3.9 (1.2) h respectively. The longer half-life in the terminal phase may be due to increased tubular reabsorption at low urinary concentrations. It was not possible to determine in this study whether the half-life was affected by changes in clearance or volume of distribution. 5 The urinary solubility of the drugs was dependent on pH. This could explain the massive macroscopic crystalluria seen in one subject after amoxycillin. Three hours after termination of the infusion, crystals could no longer be found in the sediment. There was no clinical or laboratory evidence of renal damage.

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Section: Discussionsupporting

confidence: 54%

“…The penicillins were measured as described above. The theoretical solubility (CT) of the compounds in water at different pH values was calculated from solubility data and pKa values (Tsuji et al, 1978) as…”

Section: Solubility Of the Aminopenicillins In Urinementioning

confidence: 99%

Renal excretion of intravenously infused amoxycillin and ampicillin.

Sjövall¹,

Westerlund²,

Alván³

1985

Brit J Clinical Pharma

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“…Staniforth et al (44) therefore postulated that this effect is probably due to improved solubility of amoxicillin at a higher pH. Since amoxicillin has the lowest solubility at a pH range of 4 to 6, this mechanism is not very evident (47). Surprisingly, our studies revealed an accelerated absorption and elevated maximum concentrations of amoxicillin in serum when intake followed pretreatment with antacid.…”

Section: Discussionmentioning

confidence: 47%

Influence of ranitidine, pirenzepine, and aluminum magnesium hydroxide on the bioavailability of various antibiotics, including amoxicillin, cephalexin, doxycycline, and amoxicillin-clavulanic acid

Deppermann

Lode

Höffken

et al. 1989

Antimicrob Agents Chemother

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Two randomized double-blind crossover studies and one randomized crossover study were performed to document possible drug-drug interactions between antacids (aluminum magnesium hydroxide, 10 ml per dose for 10 doses), antimuscarinic drugs (pirenzepine, 50 mg per dose for 4 doses), and H2-blockers (ranitidine, 150 mg per dose for 3 doses) and amoxicillin (1,000 mg), cephalexin (1,000 mg), doxycycline (200 mg), and amoxicillin-clavulanic acid (625 mg). Ten healthy volunteers participated in each study. Concentrations in serum and urine were measured by bioassay, and pharmacokinetic parameters were calculated by the usual open one-or two-compartment models (statistics were determined by the Wilcoxon test). The antacid, pirenzepine, and ranitidine had no influence on the bioavailability of amoxicillin, cephalexin, and amoxicillinclavulanic acid. Only small differences could be observed in the pharmacokinetic parameters, but they are not of therapeutic importance. However, the antacid caused a significant (P < 0.01) reduction in the gastrointestinal absorption of doxycycline (area under the concentration-time curve, 38.6 + 22.7 mg * h/liter, fasting; 6.0 + 3.2 mg. h/liter, with antacid), resulting in subtherapeutic levels of doxycycline.

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“…This example illustrates the time dependence of the measured solubility. Figure 1d shows the logS-pH profiles of two forms of ampicillin: anhydrous (unfilled circles) and trihydrate (filled circles) [52]. It is noteworthy that the equilibration times were 2 h in both cases.…”

Section: Atorvastatinmentioning

confidence: 99%