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%.     

Pharmacokinetics of cimetidine after subchronic administration

Summary The influence of cimetidine on its own pharmacokinetics after subchronic administration was assessed in 8 healthy volunteers, aged 26–29 years. On control Day 1, each subject received cimetidine 300 mg i.v., and serum and urine samples were obtained. Each subject was initiated on cimetidine 600 mg b.i.d. orally for 2 weeks. There were 3 further study days repeated after 1 and 2 weeks of cimetidine dosing and 1 week after stopping cimetidine. There was no significant difference in the mean total body clearance of cimetidine among the 4 study days. Mean elimination t_1/2 and V were similarly unchanged. However mean renal clearance (CL_R) and f_e were significantly increased following 2 weeks of drug dosing (CL_R 5.41 ml·min^–1 kg^–1; f_e 0.61) compared to control (CL_R 4.00 ml·min^–1·kg^–1; f_e 0.48). Although the non renal clearance was reduced from control values of 4.29 to 3.51 ml·min^–1·kg^–1 following 2 weeks of dosing the difference was not significant. Dosage adjustment of cimetidine appears unnecessary after short-term dosing in the presence of normal renal function.     

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.     

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.     

The pharmacokinetics ofα-human atrial natriuretic polypeptide in healthy subjects

Summary We have analysed the pharmacokinetics of-human atrial natriuretic polypeptide (-hANP) in healthy subjects, using a two-compartment open model following bolus intravenous injection. The plasma half-times for the fast and slow components were 1.7±0.07 min and 13.3±1.69 min respectively. V₁ (the volume of the central compartment), V_z (volume of distribution) and V_ss (volume of distribution at steady-state) were 5370±855 ml (89.5±14.3 ml·kg^–1), 32000±4620 ml (533±77.0 ml·kg^–1), and 11900±1530 ml (198±25.5 ml·kg^–1) respectively. The mean plasma clearance was 1520±121 ml·min^–1 (25.4±2.0 ml·min^–1·kg^–1.     

Relationship between renal function and disposition of oral cefixime

Summary The pharmacokinetics of cefixime following a single oral dose of 200 mg have been investigated in 6 normal subjects and in 22 patients with various degrees of renal insufficiency. Serum and urine samples were collected between 0 and 72 h and were subjected to two methods of analysis: bioassay and HPLC.There was a linear relationship between the two sets of results from 228 samples. This result suggests that none of the metabolites, which may accumulte in uraemic patients, has antibacterial activity.In normal subjects, the peak serum level (C_max) was 2.50 g·ml^–1 at 2.83 h (t_max); the apparent elimination half-life (t_1/2) was 3.73 h; the apparent total body clearance (CL·f^–1) was 154 ml·min^–1, the mean renal clearance (CL_R) was 39.1 ml·min^–1 and the apparent fraction of the dose recovered in 24 h urine was 0.22.In uraemic patients, C_max and t_max were slightly increased and t_1/2 was increased to 12–14 h in patients with an endogenous creatinine clearance below 20 ml·min^–1. The apparent volume of distribution was decreased. Apparent total and renal clearances were lower in proportion to the degree of renal insufficiency. Linear relationships were found between CL/f, CL_R and creatinine clearance (CL_CR).The findings suggest that the dose of cefixime needs to be reduced only in patients with severe renal failure.     

Changes in muscle blood flow after smoking a cigarette determined by a new noninvasive method

Summary The pharmacokinetics of the H₂-receptor antagonist famotidine, after oral administration of a 20 mg tablet, has been studied in 10 elderly patients with normal renal function (CL_CR59 ml·min^–1, Mean=80 ml·min^–1), 5 elderly patients with renal insufficiency (CL_CR38 ml·min^–1, Mean=15 ml·min^–1), and 6 healthy young volunteers.Elimination half-life in the elderly patients with renal insufficiency was significantly prolonged compared to the elderly patients with normal renal function and the young volunteers. The correlation coefficient between creatinine clearance and the elimination rate constant of famotidine was 0.672. Mean urinary recovery of unchanged drug up to 24 h in the young volunteers was 44%. The mean renal clearance of famotidine in the young volunteers (270 ml·min^–1) was substantially greater than the creatinine clearance, 128 ml·min^–1, which suggests the possibility of tubular secretion of famotidine.     

Pharmacokinetics of free and total flucloxacilin in newborn infants

Summary Flucloxacillin 50 mg/kg b.w. was administered intravenously (in combination with ampicillin/gentamicin) and orally (with amoxicillin) to 9 newborn infants (gestational age 33–41 weeks) to treat bacterial infections. The concentrations of flucloxaxillin in plasma and urine after i.v. injection were analysed according to an open two-compartment model, and the plasma protein binding of flucloxacillin and its distribution to blood cells and plasma water in whole blood were determined. Considerable differences were found from values reported in adults. The terminal half-life averaged 4 h 38 min and was significantly correlated with gestational age. Plasma clearance was low (0.744 ml·min^–1·kg^–1), due to the small renal clearance (0.182 ml·min^–1·kg^–1), whilst non-renal clearance (0.563 ml·min^–1·kg^–1) was approximately the same as in adults. The mean apparent volume of distribution of total drug (V_z) was 0.280 l/kg. The corresponding volume of distribution of unbound drug (V ₁ ^u + V ₂ ^u ) was 1.74 l/kg, which indicates considerable extravascular drug binding. The plasma protein binding of flucloxacillin (mean 86.3%) was significantly correlated with gestational age and the bilirubin/albumin concentration ratio. Bioavailability after oral administration, when corrected for changes in terminal half-life, was 47.7%, which is only slightly lower than that reported in adults. Since the plasma concentrations after both i.v. and oral administration were well above the MIC-values generally reported for Staphylococcus aureus, and since few side-effects were observed, intravenous injection or, in selected cases, oral administration of flucloxacillin appears to be a reliable therapy for the treatment of infections due to sensitive strains of S. aureus in premature newborn infants.     

The relation between type of renal disease and renal drug clearance in children

Summary It is generally assumed that the renal clearance of drugs in patients with renal impairment are affected to a similar extent regardless of the type of renal disease (intact nephron hypothesis). We have studied the effect of underlying renal disease on the pharmacokinetics of cefotaxime and desacetylcefotaxime in two groups of children (ages 7 to 16 y) with varying degrees of renal dysfunction.Patients in group 1 (n=5) had intrinsic renal disease and those in group 2 (n=5) had extrinsic renal disease, as identified by the primary renal lesion. After a single intravenous dose of cefotaxime timed blood and urine samples were collected for 24 h; cefotaxime and desacetylcefotaxime were measured by HPLC.There were no significant differences between the groups in age, body surface area, urine output, creatinine clearance, total body clearance, nonrenal clearance, renal clearance, and volume of distribution at steady state of cefotaxime, and renal clearance of desacetylcefotaxime. However, the renal clearance: creatinine clearance (CL_R:CL_CR) ratios for both cefotaxime [1.34 in group 1 vs. 0.51 in group 2] and desacetylcefotaxime [1.58 in group 1 vs. 0.75 in group 2] were statistically significant between the two groups. Group 1 patients had an average CL_R:CL_CR ratio greater than 1 for both the parent compound and the metabolite, suggesting that net tubular secretion was still intact, despite a diminished glomerular filtration rate (CL_CR=24 ml·min^–1·1.73 m^–2). In contrast, patients in group 2 (CL_CR=49) ml·min^–1·1.73 m^–2) had an average CL_R:CL_CR ratio less than 1 for both cefotaxime and desacetylcefotaxime, suggesting that renal tubular transport mechanisms did not remain functional in these patients.Our findings suggest that the effect of renal insufficiency on the renal elimination of cefotaxime and its metabolite desacetylcefotaxime may depend on the cause of renal insufficiency.     

Oral pharmacokinetics of pirenzepine in patients with chronic renal insufficiency,failure, and maintenance haemodialysis

Summary The pharmacokinetic properties of pirenzepine following administration of a single, 50 mg oral dose were evaluated in three groups of subjects: group I, end stage renal disease requiring maintenance haemodialysis (CL_CR 0 to 10 ml·min^–1); group II, moderate renal insufficiency (CL_CR 10 to 30 ml·min^–1); and group III, mild renal dysfunction (CL_CR 30 to 70 ml·min^–1). Additionally, subjects in group I received a 50 mg dose on a non-dialysis day and at least one week later, a 50 mg dose during haemodialysis.There was a linear relationship (r = 0.97) between pirenzepine renal clearance and renal function as measured by creatinine clearance. The harmonic mean terminal half-life for pirenzepine was 17.3 h in subjects with end stage renal disease, 18.0 h in subjects with moderate renal insufficiency and 14.7 h in subjects with mild renal dysfunction. Haemodialysis reduced the level of circulating pirenzepine by approximately 25%. The mean arterial to venous plasma pirenzepine ratio during hemodialysis was 1.29 (range 1.02–1.56).Based on subjective reporting of adverse experiences and clinical observation, pirenzepine appeared to have had a wide margin of safety in these patients. Dry mouth was the most frequently reported adverse experience attributable to pirenzepine administration. A reduction in dose or dosing frequency may be warranted only in end state renal disease (CL_CR 0 to 10 ml·min^–1).     

The effect of exercise on atropine pharmacokinetics

Summary Seven healthy males (19–32 y) underwent each of four separate conditions in a repeated measures design. Five of these subjects underwent an additional trial. In four of five trials subjects received 2.0 mg atropine sulfate intramuscularly in the anterolateral portion of the left thigh: at rest (T1); following completion of a single exercise (Ex) bout (T2), (Each bout consisted of 25 min of stationary cycling at 40% VO₂ max with 5 min of seated rest), prior to three Ex bouts (T3) and following one and prior to three Ex bouts (T5). Trial 4 (T4) was the same as T3 with the substitution of a saline placebo. Serum samples were collected over a 12 h period and atropine concentration was determined by RIA. Ex trials were compared to T1.Ex prior to atropine (T2) significantly decreased the mean volume of distribution (V_z, 278 vs 2321). Ex in T3 significantly decreased the serum half life (t_1/2, 4.2 vs 3.5 h), V_z (278 vs 1981), and clearance (CL, 763 vs 638 ml·min^–1) and significantly increased the peak concentration (Cp, 6.7 vs 12.3 ng·ml^–1) and area under the curve (AUC, 44.1 vs 53.1 ng·ml^–1). In T5, Ex significantly decreased the t_1/2 (3.4 h), V_z (182 l) and CL (575 ml·min^–1) and significantly increased the absorption rate constant (ka, 0.482 vs 1.1 min^–1), elimination rate constant (ke, 0.0012 vs 0.0015 min^–1), C_p (14 ng·ml^–1) and AUC (53.3 ng·h·ml^–1).These results demonstrate that moderate Ex either prior to and/or immediately following drug administration has the capacity to significantly modify atropine pharmacokinetics.Portions of this work were presented at the annual meeting of The American Society for Pharmacology and Experimental Therapeutics, Montreal, Canada, October 1988The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the opinions of the Department of the Army or the Department of Defense.     

The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites

We have studied the effect of renal impairment on the pharmacokinetics of oxcarbazepine, its active monohydroxy-metabolite (which predominates in plasma), their glucuronides, and the inactive dihydroxy-metabolite after a single oral dose of oxcarbazepine (300 mg). Six subjects with normal renal function and 20 patients with various degrees of renal impairment participated.The mean areas under the plasma concentration-time curves of oxcarbazepine and its monohydroxy-metabolite were 2–2.5-times higher in patients with severe renal impairment (CL_CR<10 ml·min^–1) than in healthy subjects. The apparent elimination half-life of the monohydroxy-metabolite [19 (SD 3) h] in these patients was about twice that in healthy subjects.The effect of renal impairment on the plasma concentrations of glucuronides was more marked. The renal clearances of the unconjugated monohydroxy-metabolite and its glucuronides (the main compounds recovered in urine) correlated well with creatinine clearance.The maximum target dose in patients with slight renal impairment (CL_CR>30 ml·min^–1) should not be changed. In patients with moderate renal impairment (CL_CR10–30 ml·min^–1) it should be reduced by 50%. In patients with severe renal impairment (CL_CR<10 ml·min^–1), the glucuronides of oxcarbazepine and its monohydroxy-metabolite are likely to accumulate during repeated administration, and dosage adjustment of oxcarbazepine in these patients could not be proposed from this single administration study.     

Pharmacokinetics of ketorolac tromethamine in humans after intravenous,intramuscular and oral administration

Summary The pharmacokinetics of ketorolac tromethamine, a potent non-narcotic analgesic agent used for relief of moderate to severe pain, has been studied in 15 healthy volunteers who received single 10 mg doses intravenously (i.v.), intramuscularly (i.m.) and orally (p.o.) in a three-way cross-over design.The kinetics of i.v. ketorolac were characterized by a terminal half-life of 5.09 h, a small plasma clearance (CL = 0.35 ml·min^–1·kg^–1) and a small tissue distribution (V_ss=0.111·kg^–1, V=0.17 l·kg^–1; mean (SD). Following i.m. and p.o. administration, peak levels of approximately 0.8 µg/ml were rapidly attained (t_max = 0.8 and 0.9 h, respectively) and the systemic bioavailability was essentially complete.     

Lack of relationship between tolbutamide metabolism and debrisoquine oxidation phenotype

Summary The oxidative metabolism of tolbutamide was studied in 13 healthy subjects of known debrisoquine phenotype. Three were poor (PM) and ten were extensive (EM) metabolisers of debrisoquine.The mean values for total plasma clearance, elimination half-life, and metabolic clearance were 0.26 ml·min^–1·kg^–1, 3.4 h, and 0.17 ml·min^–1. kg^–1 in PM subjects and 0.22 ml·min^–1·kg^–1, 4.3 h and 0.15 ml·min^–1·kg^–1 in EM subjects. Total urinary recovery (% of dose) and ratio of hydroxy- to carboxytolbutamide were 69.4% and 0.219 respectively in PM subjects and 70.9% and 0.226 in EM subjects. There were no statistically significant differences between EM and PM metabolisers for any of these parameters. In addition there was no correlation between the debrisoquine metabolic ratio and tolbutamide urinary metabolite recovery or plasma clearance.These data indicate that hydroxylation of debrisoquine and tolbutamide are not catalyzed by the same enzyme.The ratio of hydroxy- to carboxytolbutamide in our subjects, and in other recent studies, suggests that some previous publications were inaccurate and their conclusions about the genetic control of tolbutamide metabolism were incorrect.     

Sex-difference and the effects of smoking and oral contraceptive steroids on the kinetics of diflunisal

Summary The single dose pharmacokinetics of diflunisal were studied in 4 groups of 6 young volunteers: control men, control women, women taking low estrogen oral contraceptive steroids (OCS), and women smokers (10–20 cigarettes/day).The plasma clearance of diflunisal was significantly higher in men (0.169 ml·min^–1·kg^–1) and in women on OCS (0.165 ml·min^–1·kg^–1) as compared to control women (0.108 ml·min^–1·kg^–1). Partial metabolic clearances of diflunisal by the three conjugative pathways (phenolic and acyl glucuronide formation, sulphate conjugation) were all increased in men and women OCS users as compared to control women. Statistically significant increases, however, were only observed for the partial metabolic clearance of diflunisal by phenolic glucuronidation between men and women (2.91 vs. 1.85 ml·min^–1 respectively), and for the partial clearance by acyl glucuronidation between OCS users and control women (4.81 vs. 3.01 ml·min^–1 respectively).Smoking resulted in a moderate increase (35%) in plasma diflunisal clearance. However, a significant reduction in total urinary recovery of diflunisal and its glucuronide and sulphate conjugates was found in smokers (70.5% in smokers as compared to 84.2–87.2% in the 3 other study groups). Consequently, smoking may have induced hydroxylation, a minor oxidative metabolic pathway of diflunisal recently discovered in man.     

Determination of phenobarbitone population clearance values for South African children

Non-linear Mixed Effects Modelling (NONMEM) was used to estimate phenobarbitone population clearance values for South African children, using 52 serum levels gathered from 32 patients during their routine care. NONMEM was also used to evaluate the influence of fixed effects such as weight, age and concomitant medication. The final model describing phenobarbitone clearance was CL=[Exp(0.0288 Wt–2.53)] M, where CL=clearance (l·h^–1), Exp=the base of the natural logarithm, Wt=patient weight (kg) and M=a scaling factor for concomitant medication with a value of 1 for patients on phenobarbitone monotherapy, 0.62 for those receiving concomitant valproate and 0.87 for those patients receiving concomitant carbamazepine or phenytoin. Mean (95% confidence interval) phenobarbitone clearance values were 7.6 ml·h^–1·kg^–1 (6.2, 9.0 ml·h^–1·kg^–1) for the monotherapy group, 5.0 ml·h^–1·kg^–1 (4.0, 6.0 ml·h^–1·kg^–1) in the presence of concomitant valproate and 6.8 ml·h^–1·kg^–1 (5.6, 8.0 ml·h^–1·kg^–1) in the presence of concomitant carbamazepine or phenytoin. These values are similar to those previously reported from both traditional and NONMEM pharmacokinetic studies.     

Diurnal variation of methotrexate disposition in children with acute leukaemia

Summary There is recent evidence that survival is improved when maintenance therapy for acute lymphocytic leukaemia in children is given at night. We have examined the possibility that diurnal variation in methotrexate pharmacokinetics may contribute to this improvement.In 6 children with leukaemia there was a significant fall in methotrexate plasma clearance at night (from 5.6 to 4.7 ml·kg^–1·min^–1). Renal clearance of methotrexate tended to fall at night and unbound renal clearance fell significantly (from 17.5 to 8.5 ml·min^–1·kg^–1 P<0.05). Creatinine clearance did not exhibit diurnal variation, whereas there was a significant fall in the non-glomerular clearance of methotrexate (from 14.8 to 6 ml·min^–1·kg^–1).Since methotrexate is a weak organic acid, its tubular secretion depends on urinary pH. At night urinary pH is more acidic, and this may result in more reabsorption and hence reduced renal clearance.     

Disposition of oral quinine in acute falciparum malaria

Summary Plasma quinine concentrations following oral quinine sulphate 10 mg salt/kg have been measured by HPLC in 15 adult Thai patients with uncomplicated falciparum malaria. In 10 of the same patients the study was repeated in convalescence. In acute malaria plasma concentrations were approximately 50% higher than in convalescence; the mean acute peak plasma quinine concentration was 8.4 mg·l^–1 compared to 5.7 mg·l^–1 in convalescence.There was considerable variation in the rate of drug absorption, particularly in acute malaria. The mean time to peak plasma concentration was 5.9 h in acute malaria and 3.2 h in convalescence. The apparent clearance of oral quinine (CL/f) during the illness was 1.51 ml·kg^–1·min^–1, which was significantly lower than in convalescence — 2.67 ml·kg^–·min^–1. Estimated free quinine clearance was also lower in the acute phase: 30.6 compared to 49.0 ml·kg^–1·min^–1 in convalescence. Mean (SD) plasma protein binding of quinine was 94.7% in acute malaria and 92.8% in convalescence. Binding was significantly correlated with the plasma concentration of ₁ acid glycoprotein (r=0.5), which was significantly higher in the acute phase; 1.48 g·l^–1 compared to 1.05 g·l^–1 during convalescence.Oral quinine sulphate was well absorbed in uncomplicated falciparum malaria. High blood concentrations following the administration of oral quinine in acute malaria are probably related to increased plasma protein binding, lower apparent volume of distribution, and a reduction in its systemic clearance.     

Pharmacokinetics of quinine in patients with chronic renal failure

Methods: We investigated the pharmacokinetics of quinine (Qn) following administration of a single oral dose of 600 mg Qn sulphate in six male Thai patients with a moderate degree of chronic renal failure (CRF), and six male Thai subjects with normal renal function. Results: The drug was well tolerated in both groups of subjects; no major adverse reactions were observed. A marked alteration in the pharmacokinetics of Qn was found in patients with CRF compared to healthy subjects; there were six signifiicant changes in the pharmacokinetic parameters. Absorption was delayed, but increased in CRF (t_max 4.5 vs 1.6 h, C_max 6.17 vs 3.45 g·ml^–1). Total clearance was significantly reduced 0.94 vs 2.84 ml·min^–1·kg^–1, whereas V_z/f remained unchanged (1.82 vs 2.78 1·kg^–1). This resulted in the increased values of AUC and prolongation of the t_1/2z and MRT in the patients (AUC 181.5 vs 61.8 g·min^–1·ml^–1, t_1/2z 26 vs 9.7 h, MRT 36.4 vs 11.3 h). Median concentrations of plasma unbound fraction of Qn collected at 4 h after drug administration in patients and healthy subjects were 7.3 vs 9.8%, respectively.     

Polymorphic 2-hydroxylation of desipramine

Summary We have studied the clearance of monomethylaminoantipyrine (MMAAP), the pharmacologically active form of metamizol, in 46 patients in surgical intensive care with different degrees of renal dysfunction.In 23 patients without any renal impairment, mean clearance was 2.8 ml·min^–1·kg^–1. Twentyone patients with acute renal impairment had a significantly reduced clearance of MMAAP (0.83 ml·min^–1·kg^–1). There was also reduced clearance in four patients with septic shock (1.0 ml·min^–1·kg^–1).Kinetics of the metabolites of MMAAP (N-formylaminoantipyrine (FAAP), aminoantipyrine (AAP), and its secondary product N-acetylaminoantipyrine (AcAAP)) were calculated. FAAP and AcAAP showed delayed invasion, which can be explained by reduced hepatic metabolic activity. The product of N-demethylation, AAP, was not significantly altered.The delayed elimination of monomethylaminoantipyrine can be explained by reduced hepatic function in parallel with acute renal failure due to disturbed cardiovascular function caused by septic shock. This may also lead to disturbed hepatic macro- and microperfusion associated with altered oxygen supply and oxygen consumption.