α-Monofluoromethyldopa (MFMD) in combination withl-DOPA

Summary We have investigated the interaction of -monofluoromethyldopa (MFMD) with the effects of i.p. injectedl-DOPA (200 mg·kg^–1) on blood pressure and tissue catecholamines in normal and spontaneously hypertensive rats (SHR). MFMD 10 mg·kg^–1 (i.p.) effectively antagonizes thel-DOPA induced increase in heart dopamine (DA). This action is also seen after 15 or 50 mg·kg^–1. The accumulation of DA in the brain is very much reduced by MFMD 50 mg ·kg^–1 while after 15 or, especially, 10 mg·kg^–1 more DA is formed in the rrain than afterl-DOPA alone, probably due to the peripheral decarboxylase inhibition which presents morel-DOPA to the brain. We conclude that MFMD 10 mg ·kg^–1 gives a relatively selective peripheral inhibition of the decarboxylation ofl-DOPA and this dose combination was accordingly found to result in a reduction of blood pressure in conscious animals. This hypotensive response tol-DOPA was attenuated after MFMD 15 mg·kg^–1 and was absent after MFMD 50 mg·kg^–1. Interestingly, the hypotensive effect ofl-DOPA after MFMD 10 or 15 mg·kg^–1 was more pronounced in SHR.     

The pharmacokinetics of d-sotalol and d,l-sotalol in healthy volunteers

Summary The pharmacokinetics of d-sotalol has been studied in six healthy volunteers given single doses of 0.25, 0.50, 1, 2 mg·kg^–1 i.v. and one 100 mg oral dose in comparison with the kinetics of 1 mg·kg^–1 i.v. of dlsotalol.There was no significant difference in the disposition of the d-enantiomer and the racemate.The terminal half-life averaged 7.2 h, and the kinetics was linear, with a mean total clearance of 0.13 l·h^–1·kg^–1. Renal clearance of d-sotalol represented 56 to 77% of total clearance. The absolute systemic availability of oral d-sotalol was close to 100% and the elimination half-life of the oral-d-enantiomer was similar to that of the i.v. form (7.5 h).     

Comparison of verapamil and bepridil,two slow channel inhibitors,in protection against calcium-induced arrhythmias

Summary Verapamil and bepridil share the common property of antagonizing the slow inward calcium-mediated current, but bepridil has some additional antiarrhythmic properties. The efficacy of these two compounds against CaCl₂-induced arrhythmias has been compared in rats. CaCl₂ was administered i.v. by continuous infusion until death (25 mg·kg^–1·min^–1 or 40 mg·kg^–1·min^–1) or by bolus injection (160 mg·kg^–1). Bepridil (5, 10 mg·kg^–1) or verapamil (2.5,5 mg·kg^–1) were injected 10 min before CaCl₂. Bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1) prolong the survival time during CaCl₂ infusion. After pretreatment, the injection of 160 mg·kg^–1 CaCl₂ is less toxic: 25% of animals are protected by bepridil (5 mg·kg^–1), 41% by bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1).At death the myocardial Ca²⁺ level is not different in controls and pretreated animals, thus, the ratio myocardial Ca²⁺/total injected Ca²⁺ is significantly lowered by bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1). The efficacy of the two drugs on this model appears related solely to inhibition of slow inward current despite the additional antiarrhythmic profile of bepridil.     

Effect of antipyrine coadministration on the kinetics of acetaminophen and lidocaine

Summary Pharmacokinetic interactions between antipyrine and acetaminophen were evaluated in 7 healthy volunteers. On 3 occasions subjects received:1, antipyrine 1.0 g intravenously (i.v.);2, acetaminophen 650 mg i.v.;3, antipyrine 1.0 g and acetaminophen 650 mg i.v. simultaneously.Between Trials 1 and 3, antipyrine elimination t_1/2 (17.2 vs 17.4 h), clearance (0.44 vs 0.43 ml·min^–1·kg^–1) and 24-h recovery of antipyrine and metabolites (313 vs 293 mg) did not differ significantly. Between Trials 2 and 3, acetaminophen V_z was reduced (1.14 vs 1.00 l·kg^–1), t_1/2 prolonged (2.7 vs 3.3 h), clearance reduced (4.8 vs 3.6 ml·min^–1·kg^–1), and fractional urinary recovery of acetaminophen glucuronide reduced.Eight additional subjects received 50 mg of lidocaine hydrochloride i.v. in the control state, and on a second occasion immediately after antipyrine 1.0 g given i.v.The two trials did not differ significantly in lidocaine V_z (2.6 vs 2.7 l·kg^–1), t_1/2 (2.0 vs 2.4 h) or clearance (15.0 vs 13.5 ml·min^–1·kg^–1).Although acetaminophen does not alter antipyrine kinetics, acute administration of antipyrine appears to impair acetaminophen clearance, possibly via inhibition of glucuronide formation. However, antipyrine has no significant effect on the kinetics of a single i.v. dose of lidocaine.     

Pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus infection

The objective of this study was to determine the pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus (HIV) infection. After an overnight fast, a single dose of either 2 mg·kg^–1 or 8 mg·kg^–1 was administered in a suspension; five children received 2 mg·kg^–1 and four 8 mg·kg^–1 (ages 5–13 years). Blood samples were collected at various times on day 1, and once daily on days 2–7 after the dose. Fluconazole serum concentrations were measured by gas chromatography. At the dose of 2 mg·kg^–1, the C_max, AUC (0–), and t_1/2 ranged from 2.3–4.4 g·ml^–1, 84.9–136 g·h·ml^–1, and 19.8–34.8 h, respectively. At the dose of 8 mg·kg^–1 the C_max, AUC (0–), and t_1/2 ranged from 5.4–12.1 g·ml^–1, 330–684 gh·ml^–1, and 25.6–42.3 h, respectively. When compared with published data in healthy adults, fluconazole achieved similar serum concentrations in the present group of children, indicating a nearly complete degree of absorption.     

Dose-dependent absorption and elimination of cefadroxil in man

Summary The pharmacokinetic behaviour of cefadroxil was dose-dependent in healthy male volunteers following the oral administration of single doses of 5, 15, and 30 mg · kg^–1.As the dose of cefadroxil increased from 5 to 15 and 30 mg · kg^–1, the peak plasma concentrations, normalized to 5 mg · kg^–1, decreased significantly from 15.1 to 10.7 and 7.6 mg·l^–1, while the corresponding normalized areas under the plasma concentration-time curves from 0 to 2 h decreased significantly from 1258 to 946 and 801 min·mg·l^–1.When the same subjects were given 5 mg·kg^–1 of cefadroxil together with 45 mg·kg^–1 of cephalexin, the absorption of cefadroxil was slowed to a similar or greater extent than with the high dose of cefadroxil.Although the absorption rate decreased as the dose increased, the systemic availability of cefadroxil was essentially complete at all doses, as judged by the 24 h urinary recoveries of the antibiotic. Kinetic analysis of the plasma concentration-time curves gave the best fit with a zero-order followed by a first-order absorption process, consistent with saturable intestinal absorption of cefadroxil.The elimination rate of cefadroxil was directly related to dose and plasma concentrations, and the clearance at the dose of 5 mg·kg^–1 was significantly increased by the simultaneous administration of high-dose cephalexin.The renal clearance of cefadroxil ranged from 98 ml·min·l^–1 at total plasma cephalosporin (cefadroxil + cephalexin) concentrations less than 2.5 mg·l^–1 to 156 mg·l^–1 at concentrations greater than 40 mg·l^–1. These findings are consistent with saturable active gastrointestinal absorption and renal tubular reabsorption of cefadroxil, with competitive inhibition of both processes by cephalexin.     

Influence of hyperlipidic food on the kinetics of slow-release formulations of theophylline

Summary A cross-over study of kinetics has been undertaken in 12 healthy adults volunteers using two sustained-release theophylline products that allow once a day dosing (Theo-Dur tablets and Dilatrane A.P. bead filled capsules) to compare the i.v. pharmacokinetic profiles when taken with an hyperlipidic meal and a balanced standard meal. Each subject took part in four phases in randomised order, corresponding to all possible combinations of the products and the types of meal. Each phase involved a single dose of 9 to 11 mg·kg^–1 theophylline administered at 20.00 h, at the beginning of the meal, with 100 ml water.The two formulations were found to be bioequivalent with both types of meal. Taken with a balanced meal, the mean parameters were similar; for Theo-Dur and Dilatrane A.P. they were respectively:C_max: 11.32 mg·l^–1 which plateaued from 8 to 10 h after dosing and 10.9 mg·l^–1, which plateaued after 6 to 10 h; AUC 230 mg·h·l^–1 and 220 mg·h·l^–1; and MRT 18.2 h and 17.7 h. After the hyperlipidic meal the values for Theo-Dur and Dilatrane A.P. respectively, were: C_max 10.9 mg·l^–1 at 12 h and 11.3 mg·l^–1 at 10 h; AUC 237 mg·h·l^–1 and 227 mg·h·l^–1; and MRT 19.2 h and 18.9 h.In spite of a decrease in the absorption rate, which led to a shift to the right of about 2 h of the plasma concentration-time curve, the bioavailability of both formulations were not significantly modified by a hyperlipidic meal as compared to a balanced meal. The shift of the curve with fatty food was not clinically important, as there was no dumping effect.The main difference between the two formulations was seen during the absorption phase, which was linear and less variable with Dilatrane A.P. and sigmoidal with Theo-Dur. This was observed with both types of meal.     

Pharmacokinetics of ibuprofen in febrile children

Summary Ibuprofen may be an alternative to acetaminophen to control fever in children but little is known about its pharmacokinetics in pediatric patients. We studied 17 patients (age 3–10 yr) with fever; the most prevalent diagnoses were streptococcal pharyngitis and otitis media. Ibuprofen liquid was given as a single dose, 5 mg/kg (9 patients) or 10 mg/kg (8 patients). Multiple blood samples were collected over 8 hours and analyzed by HPLC.The maximum observed serum concentrations of ibuprofen ranged from 17–42 m·ml^–1 at 5 mg·kg^–1 and 25–53 m·ml^–1 at 10 mg·kg^–1 doses. Pharmacokinetics did not appear to be affected by ibuprofen dose. Mean t_max, oral clearance and elimination half life were 1.1 h, 1.2 ml·min^–1·kg^–1, and 1.6 h, respectively in patients at 5 mg·kg^–1 doses; the corresponding values were 1.2 h, 1.4 ml·min^–1·kg^–1, and 1.6 h in those receiving 10 mg·kg^–1 doses. There was no relationship between age and ibuprofen kinetics. No adverse effects occurred in any patients.These data suggest that ibuprofen pharmacokinetics may not be affected by dose between 5 and 10 mg/kg or age between 3 and 10 years.     

Pharmacokinetics of ornidazole in neonates and infants after a single intravenous infusion

Summary The single dose pharmacokinetics of ornidazole has been evaluated in 12 neonates or infants (aged 1 to 42 weeks) after the infusion of 20 mg/kg over 20 min. Plasma disposition was described by a two-compartment open model. The distribution phase was short (T_1/2 (1)=0.31 h) and was followed by an elimination phase (t_1/2 (2)=14.67 h). The mean apparent volume of distribution was 0.96 l/kg^–1. These results did not differ from data previous by reported in adults. Total plasma clearance was between 0.4 and 1.4 ml·min^–1·kg^–1. The plasma concentration 24 h after the infusion was 7.32 mg·l^–1, which was above the minimum inhibitory concentration for clinically significant anaerobic bacteria. Based on the pharmacokinetic results and residual concentrations at 24 h, a single daily infusion of ornidazole 20 mg·kg^–1 appears adequate for therapy in neonates and infants.     

Steady-state levels of pefloxacin and its metabolites in patients with severe renal impairment

Summary Twenty patients (aged 26–70 years) with severely impaired renal function received pefloxacin twice daily for 5 days as 12 mg·kg^–1 administered as a 1 h i.v. infusion, or 800 mg administered as tablets.On Day 5 the minimal and maximal plasma concentrations were 5.9 and 11.5 mg·l^–1 respectively, after the infusion, and 8.0 and 10.4 mg·l^–1, respectively, after oral administration. The steady-state level of the N-desmethyl metabolite ranged from 0.9 (infusion) to 1.2 mg·l^–1 (oral route), and that of the N-oxide metabolite ranged from 6.2 (infusion) to 9.0 mg·l^–1 (oral route). The minimal concentration of unchanged drug was related to the age of the patients (infusion), but the N-oxide concentration was influenced by the degree of renal impairment (both routes).The pefloxacin levels were similar to those achieved in healthy subjects, but reduced renal function leads accumulation of its biotransformation products, especially of the N-oxide metabolite which lacks antibacterial activity.     

Effect of sotalol on ischemic myocardial pH in the dog heart

Summary In dogs anesthetized with pentobarbital, the left anterior descending coronary artery (LAD) was occluded partially so that the LAD flow could be reduced to 1/2 to 1/3 the original flow (partial occlusion). Myocardial pH was recorded continuously by the use of a micro glass pH electrode inserted in the area to become ischemic by partial occlusion. Before partial occlusion, myocardial pH was 7.51–7.66. Partial occlusion reduced the pH by 0.63–0.72.Sotalol (5 mg·kg^–1, i.v.) increased the pH (by 0.45) that had been reduced by partial occlusion, with a marked decrease in heart rate (about 70 beats·min^–1) and a slight decrease in blood pressure (about 10 mm Hg in systolic pressure). Even when the sotalol-induced decrease in heart rate was prevented by pacing the heart, sotalol (5 mg·kg^–1, i.v.) increased the pH (by 0.43) of myocardium in which LAD was partially occluded. The pH of the non-ischemic normal heart, however, was not influenced by the injection of sotalol (5 mg·kg^–1, i.v.)It is concluded that the effect of sotalol to increase the pH of the ischemic heart is not related to the decrease in heart rate produced by the drug injection.     

Pharmacokinetics of vinorelbine in man

Summary The pharmacokinetics of vinorelbine has been investigated by a new HPLC method in 8 cancer patients receiving 8 weekly doses (30 mg·m^–2) administered by brief infusion (15 min).The plasma concentration-time curves showed a tri-exponential decay with a long terminal half-life (44.7 h) and a high volume of distribution (V_z=75.61·kg^–1). The concentrations after the 8th infusion were significantly lower than after the 1st infusion, but without significant modification of CL (1.28 l·h^–1·kg^–1) or AUC (0.80 mg·l^–1·h).The pharmacokinetic parameters exhibited wide inter-individual variations. The results are consistent with those of previous RIA studies, although the HPLC method appears to be more specific and more precise.     

Bioavailability and pharmacokinetics of oxazepam

Summary Six healthy volunteers received oxazepam 15 mg i.v. and orally at an interval of at least one week. The kinetic variables of i.v. oxazepam were: elimination half-life (t_1/2) 6.7 h, total clearance (CL) 1.07 ml·min^–1·kg^–1, volume of distribution (V_c) 0.27 l·kg^–1 (0.21–0.49) and volume of distribution at steady-state (V_ss) 0.59 l·kg^–1. The intravenous disposition of unbound oxazepam was characterized by a clearance of 22.5ml·min^–1·kg^–1 and a distribution volume of 12.3 l·kg^–1. After oral oxazepam the peak plasma level was reached in 1.7 to 2.8 h. The plasma t_1/2 at 5.8 h was not significantly different from the i.v. value. Absorption was almost complete, with a bioavailability of 92.8%. Urinary recovery was 80.0 and 71.4% of the dose after intravenous and oral administration, respectively. Renal clearance (CL_R) of the glucuronide metabolite was 1.10 ml·min^–1·kg^–1 (0.98–1.52). Oxazepam was extensively bound to plasma protein with a free fraction of 4.5%.     

The disposition of intravenous doxapram in man

Summary The pharmacokinetics of intravenous doxapram in healthy individuals is consistent with a three-compartment open model. Doxapram was administered by bolus injection (1.5 mg · kg^–1) and by intravenous infusion (6.5 mg · kg^–1 for 2 h) to 5 subjects on separate occasions. There was no significant difference in mean terminal plasma half-lives (355 and 448 min) or in mean total body clearances (5.9 and 5.6 ml · min^–1 · kg^–1) following i. v. bolus injection or infusion respectively. In 3 subjects plasma doxapram concentrations during and after i. v. infusion agreed with those predicted from pharmacokinetic values obtained from the bolus injection study. Since mean steady-state concentrations (9.9 µg · ml^–1) would be reached only after an extended interval (mean 15.2 h), a variable-rate infusion regimen was calculated to produce and maintain a concentration of 2 µg · ml^–1 from 15–25 min onwards. A regimen in which the infusion rate is reduced step-wise is recommended to achieve early near-constant plasma doxapram concentrations.     

Interaction between clonidine and physostigmine in normal rats and in rats after sinoaortic denervation

Summary Clonidine (3–30 g · kg^–1, i.v.) induced a fall in mean arterial pressure in rats after sinoaortic denervation but not in sham-operated animals. Moreover, sinoaortic denervation reduced the bradycardic action of this antihypertensive drug. Pressor and tachycardic response to physostigmine (60 g · kg^–1, i.v.) were greater in denervated than in sham-operated rats. The increase of mean arterial pressure was 26.2 ± 2.2 mm Hg in sham-operated rats (n = 12) and 53.8 ± 2.0 mm Hg in denervated rats (n = 12, P < 0.005).Pretreatment with 3 g · kg^–1 (i. v.) of clonidine did not alter the pressor response to physostigmine (60 g · kg^–1) in either of the two groups; 10 and 30 g · kg^–1 of clonidine reduced the physostigmine-induced increase of mean arterial pressure in sham-operated rats but enhanced the pressor response in denervated animals. Furthermore, an ineffective dose of physostigmine (30 g - kg^–1 i.v.) induced a pressor response after pretreatment with clonidine (10 gg · kg^–1) in denervated rats.Clonidine (10 g · kg^–1) did not affect the pressor effect of 1,1 dimethyl-4-phenylpiperazinium iodide (DMPP: 50 g · kg^–1 i.v.) or phenylephrine (4 g · kg ^–1, i.v.) in either group.The anticholinergic effect of clonidine in sham-operated rats may be explained by an inhibitory action on the release of acetylcholine in several brain structures but the facilitatory effect of clonidine observed in denervated animals is not clear. The results did not suggest a peripheral involvement in this facilitatory effect. Send offprint requests to M. A. Enero at the above address     

The disposition and protein binding of batanopride and its metabolites in subjects with renal impairment

Summary We have studied the disposition of batanopride and its three major metabolites (the erythro-alcohol, threo-alcohol, and N-desethyl metabolites) in 27 subjects with various degrees of renal function after intravenous infusion of a single dose of 3.6·mg·kg^–1 of batanopride over 15 min.The subjects were assigned to one of three treatment groups: group 1, normal renal function (creatinine clearance 75 ml·min^–1·1.73 m^–2; n=13); group 2, moderate renal impairment (creatinine clearance 30–60 ml·min^–1·1.73 m^–2; n=8); group 3, severe renal impairment (creatinine clearance 30 ml·min^–1·1.73 m^–2; n=6).The terminal half-life of batanopride was significantly prolonged from 2.7 h in group 1 to 9.9 h in group 3. The renal clearance of batanopride was significantly lower in group 3 (25 ml·min^–1) compared with group 1 (132 ml·min^–1).There were no differences in plasma protein binding or steady-state volume of distribution of batanopride among the groups.There were significantly lower renal clearances for all three metabolites in groups 2 and 3 compared with group 1. The half-lives of all three metabolites were significantly prolonged in group 3 compared with group 1.The dose of batanopride may need to be reduced in patients with creatinine clearances less than 30 ml·min^–1·1.73 m^–2 to prevent drug accumulation and avoid possible dose-related adverse effects.     

Pharmacokinetics of ranitidine in patients undergoing haemofiltration

Summary The pharmacokinetics of ranitidine was investigated in 11 patients with acute or end stage renal failure during haemofiltration. Each patient received 50 mg ranitidine i.v.The mean distribution and elimination half lives were 0.13 and 2.57 h, respectively. The total body clearance (CL) and volume of distribution (V_z) were 298 ml·min^–1 (5.19 ml·min^–1·kg^–1) and 1.081·kg^–1, respectively. About 17.1% of the administered dose was removed by haemofiltration (in approximately 201 filtrate). Five of the patients still had some urine output and they excreted 0.1 to 11.8% of the dose in urine in 24 h. The haemofiltration clearance was 66.9 ml·min^–1 at a filtrate flow rate of 86 ml·min^–1, corresponding to a mean sieving coefficient of 0.78 (n=6). As plasma concentrations were still in an effective range after haemofiltration, dose supplementation is not recommended.     

Pharmacokinetics of ciprofloxacin tablets in renal failure; influence of haemodialysis

Summary The pharmacokinetics of ciprofloxacin has been studied after a single oral dose of 500 mg given to 5 normal subjects (N) and to 15 patients grouped according to their residual renal creatinine clearance: Group I, 8–30 ml·min^–1, Group II, <8 ml·min^–1, and Group III, haemodialysed patients studied twice — during an interdialysis period (IIIa) and in a 4 h haemodialysis session (IIIb). Ciprofloxacin was assayed by reverse phase HPLC using a spectrofluorimetric detection. The peak plasma concentration (2–5 mg·l^–1) was reached within 2 h after drug administration. Apparent volume of distribution, 6.6 (N), 5.0 (I), 2.7 (II) and 4.2 (IIIa) l·kg^–1 and total plasma clearance, 770 (N), 440 (I), 378 (II) and 314 (IIIa) ml·min^–1 were decreased in relation to the degree of renal impairment. Mean plasma half-lives for patients in the 4 groups were 7.3 (N), 10.4 (I), 7.2 (II) and 9.3 (IIIa) h. In groups N, I and II, 40, 16 and 8% of the administered dose was eliminated through the kidney, with mean renal clearances of 305±63,61±21 and 21±3 ml·min^–1. A linear relationship was found between the renal clearance of ciprofloxacin and the glomerular filtration rate (r=0.75,n=15). Ciprofloxacin was partly removed by haemodialysis (IIIb): the dialyser extraction ratio was 23% and the dialysis clearance was 40 ml·min^–1.     

Drug monitoring of quinine by HPLC in cerebral malaria with acute renal failure treated by haemofiltration

Summary The monitoring of quinine by HPLC in 3 patients suffering from cerebral malaria with acute renal failure and treated by haemofiltration is reported.The recommended dose of quinine in this situation is reduced to 10 to 15 mg·kg^–1·day^–1. However, in the first patient, when given quinine 10 mg kg^–1·day^–1 the plasma concentration was mainly below the recommended therapeutic range of 5 to 15 mg/l. In consequence, the dose of quinine in the second patient was elevated to quinine dihydrochloride 15.1 mg·kg^–1·day^–1 which produced plasma concentrations in the low therapeutic range. In the third patient, an unreduced dose of quinine dihydrochloride 25.7 mg·kg^–1·day^–1 was employed, resulting in plasma concentrations above 15 mg/l, which is generally assumed to be toxic, although, no sign of acute quinine toxicity was seen.The antimalarial effect in all three patients was satisfactory. Quinine was estimated in the haemofiltrate in two patients and was found to be below the limit of sensitivity (0.25 mg/l). Plasma quinine did not change during or shortly after haemofiltration.It is concluded that in case of acute renal failure in cerebral malaria the dose of quinine should be reduced, but that the common recommendation of 10 to 15 mg·kg^–1·day^–1 may be too low, and that haemofiltration has no marked influence on the total body clearance of quinine.     

Pharmacokinetics and tissue concentrations of ceftazidime in burn patients

Summary The pharmacokinetics and tissue concentrations of ceftazidime have been investigated in 8 patients with severe burns (20–80% of body surface area) undergoing skin transplantation 2 to 21 days after injury. Two prophylactic doses of ceftazidime were administered as 1 g i.v. bolus injections with an 8 h interval. Blood, urine, burn blister fluid and tissue were frequently sampled and drug concentrations were analyzed by HPLC. The kinetics of ceftazidime was the same after each dose.In these patients the pharmacokinetics of ceftazidime was greatly altered from that in other patients and there was much interindividual variation. The mean ceftazidime elimination half-life, apparent volume of distribution and total clearance were: 2.7 h, 30.91 (0.38 l·kg^–1) and 139 ml·min^–1, respectively. A linear correlation was found between creatinine clearance and the renal clearance of the ceftazidime, the mean values being 108 and 95 ml·min^–1, respectively. No correlation was found between creatinine clearance and the total clearance of ceftazidime. The mean percentage urine recovery was 69% of the dose. Tissue and burn blister fluid concentrations were above the MIC, and ranged from 40.0 to 3.1 mg·kg^–1. A substantial increase in the apparent volume of distribution and non-renal clearance of ceftazidime was observed, probably due to increased capillary permeability and drug loss through the wound surface replacement of prior to surgery and subsequently to lost and blood fluid.