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.     

Paracetamol disposition in Thai patients during and after treatment of falciparum malaria

Investigations in animals have suggested that conjugation of paracetamol may be reduced in malaria. We have measured plasma concentrations and the urinary excretion of paracetamol and its phase II metabolites in eight Thai patients during uncomplicated falciparum malaria and in convalescence, following a 1000 mg single oral dose.The apparent oral clearance (Malaria, 3.6; Convalescence, 3.9; ml·min^–1·kg^–1), the elimination half-life (Malaria, 3.8; Convalescence, 3.7 h) and apparent volume of distribution (Malaria, 1.2; Convalescence, 1.2; l·kg^–1) of paracetamol were similar during malaria and convalescence. In addition, the urinary excretion of paracetamol and its major phase II metabolites and their formation clearances from paracetamol were not significantly different between the two study phases.These data show that clinical malaria infection has no effect on the conjugation of paracetamol in man.     

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.     

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.     

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.     

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.     

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 concentration-dependent disposition and kinetics of inulin

Summary The disposition of inulin was studied in 30 healthy male and 10 healthy female volunteers, and 10 patients with stable chronic renal failure (mean creatinine clearance 45 ml·min^–1) following intravenous infusion of 70 mg·kg^–1 over 5 min.Plasma concentrations fell rapidly initially but the rate of decline decreased continuously over 8 h and a linear terminal elimination phase could not be identified. Inulin was excreted rapidly by the subjects with normal renal function and 97.3% of the dose was recovered in the urine in 8 h. There was a progressive highly significant fall in the renal clearance of inulin after 2 h as plasma concentrations fell below about 150 mg·l^–1. Six to 8 h after administration the clearance was less than 50% of the initial value in the healthy volunteers and the corresponding fall in the renal patients was 33%.The concentration-dependent renal clearance of inulin was confirmed in step-up and step-down constant infusion studies in which clearances were measured at mean plasma concentrations ranging from 35.2 to 186.7 mg·l^–1. These studies virtually excluded time, changes in posture and urine flow rate as important factors. There was no statistically significant fall in clearance during the first 2 h and kinetic analysis was based on data obtained over this time. Under these conditions the mean plasma half life, volume of distribution (V_ss) and total body clearance of inulin in the healthy males, healthy females and patients with chronic renal failure were 73.2, 65.5 and 172.4 min, 10.5, 9.6 and 8.81·70 kg^–1 and 113.3, 111.5 and 43.3 ml·min^–1·70 kg^–1 respectively. There were no sex differences in any of the kinetic variables.The mechanism of the concentration-dependent clearance of inulin is unknown but the findings are consistent with saturable renal tubular reabsorption. Care is required with the use of inulin for measurement of the glomerular filtration rate by the single injection technique.     

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.     

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.     

The effects of posture on the pharmacokinetics of intramuscular benzylpenicillin

Summary Previous reports have produced conflicting results as to whether changes in posture affected the pharmacokinetics of the penicillins.We have studied the pharmacokinetics of intramuscularly administered benzylpenicillin in normal subjects during bedrest and ambulation and compared it with data obtained following intravenous administration of the same dose to the same subjects under the same conditions. The values of area under the curve, total clearance, mean residence time and renal clearance found during ambulation were 1175 (min·min·l^–1), 488 (ml·min^–1), 101 (min), and 264 (ml·min^–1) (means). The corresponding values for bedrest were 1032 (min·mg·l^–1), 544 (ml·min^–1), 96.7 (min), and 315 (ml·min^–1).There was a significant difference between the areas under the curve with change of posture but not between any of the other pharmacokinetic variables. The differences observed in this study are unlikely to be of clinical relevance.We suggest that the differences between the results of this study and those of previous studies may be related to the level of exercise undertaken by the subjects in the various studies.     

Sex-related differences in theophylline pharmacokinetics

Summary Theophylline pharmacokinetic parameters were compared in healthy males and healthy premenopausal females who were matched for age and smoking status. Twenty-four subjects (including five smokers and seven non-smokers of each sex) received a single dose of aminophylline 6 mg·kg^–1, orally or by intravenous infusion. Theophylline half-life was significantly shorter in female non-smokers (FNS) versus male non-smokers (MNS), (FNS=6.0 h; MNS=9.3 h), and in female smokers (FS) versus male smokers (MS), (FS=4.6 h; MS=6.3 h). Total body clearance was significantly different in FNS versus MNS, (FNS=43.8 ml·min^–1·^–1.73 m^–2; MNS=37.4 ml·min^–1·1.73 m^–2), but did not reach statistical significance in FS vs. MS, (FS=64.2 ml·min^–1·l^–1·1.73 m^–2; MS=53.1 ml·min^–1·1.73 m^–2). Volume of distribution did not differ significantly between groups.Sex differences in theophylline pharmacokinetics exist and may reflect differences in drug metabolism.     

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 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.     

Pharmacokinetic characteristics and tolerability of a novel intravenous immunoglobulin preparation

In two independent trials 10 and 12 healthy volunteers received the novel intravenous immunoglobulin (IVIG) preparations BT 511 and BT 507, respectively. BT 511 contains 5 g human plasma proteins per 100 ml, more than 95% of which are immunoglobulins of the G class (IgG). BT 507 contains in addition 61 IU antibody against hepatitis B surface antigen (anti-HBs)·ml^–1. In trial I volunteers received 4.0 ml/kg (n+4) and 8.0 ml·kg^–1 (n+6) BT 511 to study the tolerability and the magnitude of the increase in immunoglobulins in plasma as well as their decline over 1 month. After administration of the lower dose, plasma IgG increased from 10.7 to 14.7 g·l^–1 directly after the infusion. Following the 8.0 ml·kg^–1 dose a more pronounced increase from 12.4 to 21.2 g·l^–1 was observed. No adverse events occurred. After 1 month IgG concentrations had almost reached baseline values at 12.2 g·l^–1 in the 4.0 ml·kg^–1 group, but were still significantly increased at 15.2 g·l^–1 after the high dose. There was a linear correlation between the maximal IgG plasma concentration and the subsequent decline of IgG during the 29-day observation period. After administration of BT 507 maximal anti-HBs concentrations of 1778 mU·ml^–1 occurred 1.4 h after termination of the infusion. The terminal elimination half-life was 22.4 days, and total clearance and volume of distribution were determined to be 0.122 ml·min^–1 and 5.41, respectively. The pharmacokinetic parameters calculated for anti-HBs as an indicator of IgG were in accordance with the pharmacokinetic behaviour of native IgG.     

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.     

Simvastatin reduces plasma lipid levels and improves insulin action in elderly,non-insulin dependent diabetics

Summary Twelve elderly non-insulin dependent diabetic patients took part in a double-blind, cross-over, randomized study comparing simvastatin 30 mg/day and placebo. Each treatment period lasted 3 weeks and was separated by a 3 week wash-out period. At the end of each treatment period all subjects underwent in randomized order an oral glucose tolerance test (OGTT; 75 g) and an euglycaemic hyperinsulinaemic (50 mU/kg·h) glucose clamp.Simvastatin compared to placebo significantly reduced plasma total cholesterol (7.9 vs 5.3 mmol·l^–1), LDL-cholesterol (7.2 vs 4.3 mmol·l^–1), triglycerides (2.9 vs 2.1 mmol·l^–1), free fatty acids (1106 vs 818 mmol^–1) and glucose (7.4 vs 6.6 mmol·l^–1) levels.After simvastatin, and in the last 60 min of the glucose clamp, there was an improvement in the action of insulin as demonstrated by stronger inhibition of hepatic glucose output (2.7 vs 5.2 mol·kg^–1·min^–1) and stimulation both of the glucose disappearance rate (26.3 vs 19.5 mol·kg^–1·min^–1) and glucose metabolic clearance rate (4.3 vs 3.6 ml·kg^–1·min^–1).The changes in glucose turnover parameters were significantly correlated with basal plasma free fatty acids and were independent of plasma glucoregulatory hormones. In conclusion, simvastatin seems to exert beneficial effects both on lipid and glucose metabolism.     

Renal clearance of sulphinpyrazone in man

Summary Six healthy young volunteers received a single dose of sulphinpyrazone 200 mg p.o. Plasma concentration and urinary excretion rate curves showed large intersubject variation for sulphinpyrazone and its metabolites. The sulphide metabolite could only be detected in plasma and not before 3–7 h after ingestion. The total recovery in urine of all compounds varied from 30–56% of the dose.In two subjects the mean residence time of sulphinpyrazone was twice as long as in the other subjects (10.4 h compared with 4.6 h), but the area under the plasma concentration-time curve was comparable to that in the others (mean: 3.0 mg·ml^–1·min), indicating that drug absorption was quantitatively similar but delayed.The renal clearance of sulphinpyrazone varied from 14–40 ml·min^–1 (mean: 28 ml·min^–1).In view of the very high plasma protein binding of sulphinpyrazone, active tubular secretion is the predominant mechanism in its renal clearance. The same holds for the sulphone metabolite, which has a mean renal clearance of 24 ml·min^–1, and even more for the p-hydroxysulphinpyrazone metabolite, which has a renal clearance of 118 ml·min^–1.No unambiguous evidence was found in favour of concentration-dependent renal clearance of sulphinpyrazone or its metabolites over the concentration range studied. The renal clearance, especially of sulphinpyrazone, appeared to be dependent on urine pH and not on urine flow rate.     

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 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.