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.     

Single- and multiple-dose pharmacokinetics of terodiline in geriatric patients

Summary As a target group, geriataric patients were selected for pharmacokinetic studies with terodiline (Mictrol), an anticholinergic and calcium antagonist drug effective in the treatment of urinary incontinence. The single-dose kinetics in the geriatric patients (mean age 82 years) differed significantly from that previously found (Hallén et al. 1987) in healthy volunteers (mean age 35 years). There were higher peak serum concentrations (110 vs 79 µg·l^–1), increased half-life (189 vs 60 h), lower renal clearance (4.0 vs 10.9 ml·min^–1) and lower total clearance (29 vs 75 ml·min^–1). Multiple-doses of 12.5 mg b.d. for 6–8 weeks resulted in a mean steady-state concentration of 642 µg·l^–1, which was in agreement with the single dose parameters. The studied geriatric patients can be characterized not only as old, but also as frail, bedridden, having several diseases and polymedicated. The differences in pharmacokinetics between younger and elderly subjects can be attributed to a variety of complex factors, which may alter the clearance and/or the volume of distribution.     

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.     

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     

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.     

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.     

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.     

The effect of a low dose of quinidine on the disposition of flecainide in healthy volunteers

Summary We have studied the effects of quinidine on ECG intervals and on the pharmacokinetics of flecainide and its two metabolites in 6 healthy men in an open randomized crossover study. Flecainide acetate (150 mg) was given as a constant rate i. v. infusion over 30 min.Quinidine (50 mg orally), given the previous evening, did not change the volume of distribution of flecainide (7.9 vs 7.41·kg^–1), but significantly increased its half-life (8.8 vs 10.7 h). This was attributable to a reduction in total clearance (10.6 vs 8.1 ml·min^–1·kg^–1), most of it being accounted for by a reduction in non-renal clearance (7.2 vs 5.2 ml·min^–1·kg^–1). The excretion of the metabolites of flecainide over 48 h was significantly reduced.These findings suggest that quinidine inhibits the first step of flecainide metabolism, although it may also reduce its renal clearance, but to a lesser extent (3.5 vs 2.9 ml·min^–1·kg^–1).The effects of flecainide on ECG intervals were not altered by quinidine.Thus, quinidine tends to shift extensive metabolizer status for flecainide towards poor metabolizer status and may also alter its renal excretion.     

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.     

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.     

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.     

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.     

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 and effects of frusemide in patients with the nephrotic syndrome

Summary The renal handling and effects of an intravenous bolus of frusemide with and without plasma volume expansion with dextran or albumin, and with large variations in plasma albumin concentration, have been studied in five patients with the nephrotic syndrome.Decreased renal sensitivity to frusemide was found in only one patient, who also had hypovolaemia and an activated renin-angiotensin-aldosterone system. Plasma volume expansion increased the diuresis but not the saluresis, and slightly increased renal sensitivity to frusemide.An increase in albuminuria after albumin infusion did not reduce the sensitivity to frusemide. A decrease in plasma albumin concentration from 33 g·l^–1 after albumin infusion to 23 g·l^–1 after infusion of dextran caused a substantial increase in the renal clearance (from 84 to 123 ml·min^–1), non-renal clearance (from 72 to 138 ml·min^–1), and apparent volume of distribution (from 13 to 23 l) of frusemide, probably as a consequence of an increase in the unbound fraction. The rate of urinary excretion of frusemide was highest after albumin infusion, despite the fact that its renal clearance was lowest then.     

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.     

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.     

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.     

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.     

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.     

Effect of loperamide on jejunal electrolyte and water transport,prostaglandin E 2-induced secretion and intestinal transit time in man

Summary Jejunal perfusion was performed in 12 healthy volunteers to evaluate the dose dependent effects of loperamide on intestinal absorption, stimulated secretion and transit.In 6 volunteers intestinal perfusion of the jejunal segment with isotonic NaCl solution was followed by addition of loperamide in increasing doses (2–8 mg·l^–1). The volunteers were pretreated with 1 mg·l^–1 prostaglandin E2 (PgE2) in the perfusate before addition of 4 mg·l^–1 loperamide. Phenolsulphonphtalein (PSP) boluses (2 ml) were given to measure mean transit time (MTT).Loperamide 2 mg·l^–1 converted the minor secretion after perfusion with the standard solution (water –1.45 ml·min^–1, Na –0.09 and Cl –0.04 mmol·min^–1) to absorption (water 0.93 ml·min^–1, Na 0.23, Cl 0.25 mmol·min^–1) within 15 min. Higher doses of loperamide did not increase absorption.The addition of PgE2 induced net secretion of water (–4.48 ml·min^–1) and electrolytes (Na –0.57, Cl –0.51 mmol·min^–1). Loperamide 4 mg·l^–1 significantly diminished the PgE2-induced net secretion by approximately 50%.Loperamide dose dependently increased the MTT from 6 (2 mg·l^–1) to 13.3 min (8 mg·l^–1). MTT was still delayed 60 min after a wash out period (10.5 min).It is concluded that loperamide had a dual effect or intestinal activities stimulating absorption and prolonging intestinal transit time with rising doses.