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).     

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.     

Steady-state pharmacokinetics of nefazodone in subjects with normal and impaired renal function

The steady-state pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were compared in subjects with normal and impaired renal function. Patients: The Study was of parallel group design which included 7 subjects with normal (NOR) renal function, CL_CR72 ml·min^–1·1.73 m^–2, 6 with moderate (MOD) renal impairment, CL_CR 31–60 ml·min^–1·1.73 m^–2 and 9 with severe (SEV) renal impairment, CL_CR30 ml·min^–1·1.73 m^–2. Subjects in each renal function group received a 100-mg oral dose of nefazodone hydrochloride BID for 7 days and a single morning dose on day 8. Starting 48 h after the last 100-mg dose, 200-mg doses were administered on a similar schedule to 3, 4 and 3 subjects from each renal function group (NOR, MOD and SEV, respectively). Single trough blood samples just prior to each morning dose (C_min) and serial samples after the dose on day 8 were obtained at each dose level for pharmacokinetic analysis. Plasma samples were assayed by a specific HPLC method for NEF, HO-NEF and mCPP.The CMIN data indicated that steady state was attained by the third day of BID administration of both the 100- and 200-mg doses of nefazodone, regardless of degree of renal function. Both NEF and HO-NEF attained steady-state C_max within 2 h after administration of nefazodone; t_max for mCPP was less defined and more delayed. HO-NEF and mCPP plasma levels were about 1/3 and <1/10 those of NEF, respectively, regardless of the status of renal function. Steady-state systemic exposure of NEF and HO-NEF, as reflected by AUC and C_max, and elimination t_1/2 values did not differ significantly among renal function groups. Conclusion: The study results suggest that dose adjustments may not be necessary, but nefazodone should be used with caution in the presence of severe renal impairment.     

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.     

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.     

Sensitivity of residual nephrons to high dose furosemide described by diuretic efficiency

Ten haemodialysis (HD) patients with a median residual creatinine clearance (CL_CR) of 1.9 ml·min^–1·1.73 m^–2 (range 0.6–5.3) were treated with oral furosemide (F) 2.0 g. Overall-efficiency (O-E, daily sodium excretion/total urinary F) and total-efficiency (-E, increase in daily sodium excretion/total urinary F) were measured on the last 24 hours of each interdialysis interval. In addition, O-E was measured during the complete interdialysis interval in 10 HD patients with a median CL_CR of 5.6 ml·min^–1·1.73 m^–2 (range 0.7–6.8) treated for 1 year with a fixed oral dose of F between 250–1000 mg (median 625 mg).In the short study the median O-E was 10.6 mmol·mg^–1 (range 1.9–22.0) and -E 6.2 mmol·mg^–1 (range 1.3–11.2). The fractional excretion of sodium FE_Na was significantly increased from 9.6% (range 4.1–22.9) to 27% (range 14.6–56.2) during F treatment. A positive correlation was found between the basal FE_Na and -E. In the long-term study median O-E was 6.4 mmol·mg^–1. O-E and FE_Na showed no change over time although median RCC decreased from 5.6 to 1.9 ml·min^–1·1.73 m^–2 and median F excretion from 11.8 to 7.5 mg per day.It can be concluded that diuretic efficiency in haemodialysis patients is dependent on FE_Na and the state of hydration during the interdialysis interval.     

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.     

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 imidapril and its active metabolite imidaprilat following single dose and during steady state in patients with chronic renal failure

Objective: An open study on the single dose and steady-state pharmacokinetics of imidapril, a novel prodrug-type angiotensin-converting enzyme (ACE) inhibitor, and its active metabolite imidaprilat was conducted in eight patients with moderate chronic renal failure [mean creatinine clearance (CL_CR) 64 ml · min⁻¹; range 42–77 ml · min⁻¹], eight patients with severe chronic renal failure (mean CL_CR, 18 ml · min⁻¹; range 11–29 ml · min⁻¹) and eight healthy volunteers with normal renal function. Subjects received an oral dose of 10 mg imidapril once per day for 7 days. Results: No statistical differences of either maximum concentration (C_max) or the area under the curve (AUC) were found between patients with moderate renal failure and healthy subjects. However, C_max and AUC for both imidapril and imidaprilat were significantly higher in patients with severe renal impairment than in healthy volunteers. There were no clinically relevant differences among the three subject groups with regard to total urinary excretion of both imidapril and imidaprilat. Conclusion: The smallest imidapril dose which is clinically effective should be used in patients with severe renal insufficiency. Received : 11 July 1997 / Accepted in revised form : 6 October 1997     

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 famotidine,a new H2-receptor antagonist,in relation to renal function

Summary The pharmacokinetics of a new, potent H₂-receptor antagonist, famotidine, 20 mg i.v. was studied in 7 subjects with normal renal function and in 24 patients with varying degrees of renal impairment. The volume of distribution at steady state was 1.14 l/kg in normal subjects and was not altered in renal failure. The half-life of elimination was 2.59 h in normal subjects and was unchanged in mild renal failure (creatinine clearance, CL_CR 90–60 ml/min/1.48 m²) but was increased to 4.72 h in moderate renal failure (CL_CR 60–30 ml/min/1.48 m²), and to 12.07 h in severe renal failure (CL_CR below 30 ml/min/1.48 m²). The cumulative urinary excretion and renal clearance of famotidine were correspondingly reduced in patients with impaired kidney function. In normal subjects and in patients with mild to moderate renal failure, about 70% of famotidine was excreted through the kidney, mainly by tubular secretion. In patients with a CL_CR above 60 ml/min/1.48 m² the normal daily dose of famotidine can be employed, but in those with a CL_CR between 60 and 30 ml/min/1.48 m² the dose should be reduced by half, and in patients with a CL_CR below 30 ml/min/1.48 m² a reduction by three quarters of the normal dose is recommended.     

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.     

Raised plasma levels of atrial natriuretic factor in cardiac allograft recipients: evidence of increased cardiac secretion and decreased renal clearance

The mechanism(s) causing high levels of plasma atrial natriuretic factor (ANF) in cardiac allograft recipients is(are) unclear. The kidney is important for the clearance of ANF and renal function may decline with cyclosporin A therapy in these patients. The relationship between plasma ANF level and renal function and also the pharmacokinetics of a continuous infusion of ANF (15.5 ng·kg^–1·min^–1 for 60 min) was examined in 6 cardiac allograft recipients on cyclosporin A therapy.Resting plasma ANF levels were significantly higher in these patients than in 8 healthy subjects (71 vs. 21 ng·l^–1). Both effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were significantly lower in these patients than in healthy subjects (215 vs. 617 ml·min^–1 and 55 vs. 102 ml·min^–1 respectively). There was a significant inverse correlation between plasma ANF and ERPF (r=-0.86) and between plasma ANF and GFR (r=-0.81). During the period of ANF infusion, steady state plasma ANF levels were significantly higher in cardiac allograft recipients. Total body clearance of ANF was marginally lower in these patients than in healthy subjects (60 vs. 10.0 l·min^–1) although this difference did not reach statistical significance. Derived endogenous secretion rate of ANF was threefold higher in patients when compared to healthy subjects (633 vs. 208 ng·min^–1).We have therefore shown that cardiac allograft recipients on cyclosporin A have elevated plasma ANF levels and also decreased renal function. Pharmacokinetic analysis have shown that this increase in plasma ANF levels is due more to increased ANF secretion than to decreased ANF clearance in these patients.     

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.     

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 cefonicid in children

Summary The pharmacokinetics of cefonicid was studied in 17 children requiring antibiotic treatment for respiratory or urinary tract infections. After informed consent had been obtained from the parents, a single dose of cefonicid 50 mg/kg/body weight was given by intramuscular injection.The mean peak serum concentration of 212.63 µg/ml was reached at 1.00 h, as absorption occurred at a very fast rate with a mean constant of 3.24 h^–1. Mean values for half-life, apparent volume of distribution (V_z), total body clearance (CL), and renal clearance (CL_R) were 3.24 h, 0.21 l·kg^–1, 16.67 ml·min^–1 and 13.60 ml·min^–1 respectively. There was an inverse relationship between age and V_z, whereas CL and CL_R were positively correlated with age. Cefonicid concentrations in urine were many times higher than the MICs of susceptible strains of bacteria.The study demonstrated that i.m. cefonicid 50 mg·kg^–1 gave serum concentrations well within the therapeutic range for susceptible bacteria, and that its pharmacokinetic properties allow single daily doses to be used to treat infections in children.     

Pharmacokinetics of pefloxacin in renal insufficiency

Summary The kinetics of pefloxacin has been studied after a single intravenous infusion of 8 mg·kg^–1 in 15 male patients with various degrees of renal failure. No difference in distribution or elimination of the drug was observed between patients with mild or severe renal impairment. The mean volume of distribution (Vd area) and the mean plasma clearance were 2.03l·kg^–1 and 121.3 ml·min^–1, respectively. The mean apparent elimination half-life was 13.5 h. These values are close to those observed in healthy subjects. No accumulation of the active N-desmethylmetabolite was observed in cases of severe failure as compared to mild impairment; its apparent elimination half-life was about twice that of the parent drug. The efficacy of a 4 h haemodialysis in 6 additional anuric subjects done to remove pefloxacin from the body was poor.     

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%.     

Polymorphic flecainide disposition under conditions of uncontrolled urine flow and pH

Summary The pharmacokinetics of R- and S-flecainide have been determined in five poor (PM) and five extensive (EM) metabolisers of sparteine/debrisoquine under conditions of uncontrolled urine flow and pH. The half-lives of R- and S-flecainide in PMs (R 19.3 h; S 16.1 h) were approximately twice those observed in EMs (R 8.8 h; S 9.1 h). The apparent oral clearances of R- and S-flecainide were lower in PMs (R 313 ml·min^–1; S 379 ml·min^–1) than in EMs (R 783 ml·min^–1; S 828 ml·min^–1). The renal clearance, however, was comparable for both enantiomers in both EMs and PMs, and therefore the phenotypic differences in flecainide disposition observed must be due to differences in metabolic clearance. The nonrenal clearance of both enantiomers was significantly lower in poor (R 123 ml·min^–1; S 201 ml·min^–1) relative to extensive metabolisers (R 533 ml·min^–1; S 586 ml·min^–1). The partial clearance to the two major metabolites meta-O-dealkylated flecainide (MODF) and the meta-O-dealkylated lactam of flecainide (MODLF) was significantly lower in poor (62 ml·min^–1) than extensive (267 ml·min^–1) metabolisers.The impairment in flecainide metabolism in poor metabolisers of sparteine/debrisoquine has therefore been confirmed. Under conditions reflecting the clinical situation the difference in disposition between EMs and PMs would be considerable. However, it may be predicted that at standard doses concentrations greater than 1000 ng·ml^–1 would not be attained in the PMs studied. The serum protein binding of R- and S-flecainide was studied in each subject and no differences between the enantiomers or the phenotypes were observed (Free fraction EM: R 0.43; S 0.42; PM R: 0.46; S: 0.46). Enantioselective disposition was noted in all PMs studied, due to a significantly lower nonrenal clearance of the R-enantiomer. In extensive metaboliser subjects, considerable interindividual variation in the enantioselective disposition of flecainide was noted, ranging from metabolism favouring either enantiomer to the absence of any selectivity.Presented in part at the 23rd Annual Meeting of the Australasian Society of Clinical and Experimental Pharmacologists, Sydney, 4–6 December, 1989     

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.