Aims To investigate the pharmacokinetics of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) in healthy volunteers after the administration of morphine by subcutaneous bolus injection (s.c.b.) and subcutaneous infusion (s.c.i.) over 4 h, and to compare the results with the intravenous bolus (i.v.) administration of morphine. Methods Six healthy volunteers each received 5 mg morphine sulphate by i.v., s.c.b. and short s.c.i. over 4 h, on three separate occasions, in random order, each separated by at least 1 week. Plasma samples were assayed for morphine, M6G and M3G. Results After i.v. morphine, the concentrations of morphine, M6G and M3G and their pharmacokinetic parameters were similar to those we have observed previously, in other healthy volunteers (when standardized to nmol l x 1 , for a 10 mg dose to a 70 kg subject). After s.c.b. morphine, similar results were obtained except that the median t max values for morphine and M3G were signi®cantly longer than after i.v. morphine (P<0.001 and P<0.05, respectively), with a trend to a longer t max for M6G (P =0.09). The appearance half-lives after s.c.b. morphine for M6G and M3G were also signi®cantly longer than after i.v. morphine (P =0.03 and P<0.05, respectively). Comparison of log-transformed AUC values indicated that i.v. and s.c.b. administration of morphine were bioequivalent with respect to morphine, M6G and M3G. In comparison with i.v. morphine, morphine by s.c.i. was associated with signi®cantly longer median t max values for morphine (P<0.001), M6G (P<0.001) and M3G (P<0.05), and the mean standardized C max values signi®cantly lower than after both i.v. and s.c.b. morphine (morphine P<0.001, M6G P<0.001 and M3G P<0.01 for each comparison). Comparison of log-transformed AUC values after i.v. and s.c.i. morphine indicated that the two routes were not bioequivalent for morphine (logtransformed AUC ratio 0.78, 90% CI 0.66±0.93), M6G (0.72, 90% CI 0.63±0.82), or M3G (0.65, 90% CI 0.54±0.78). A small stability study indicated no evidence of adsorptive losses from morphine infused over 4 h using the infusion devices from the study. Conclusions Although bioequivalence was demonstrated between the s.c.b. and i.v. routes of morphine administration, the bioavailabilities of morphine, M6G and M3G after s.c.i. were signi®cantly lower than after i.v. administration. However, despite this, the study demonstrates that the subcutaneous route is an effective method for the parenteral administration of morphine.

1 It is well‐known that considerable variability and unpredictability in serum concentrations results from orally administered erythromycin. 2 Disposition kinetics and their variability were studies in 24 healthy subjects after a single dose of erythromycin lactobionate and four doses were studied to evaluate dose‐related variability in five other subjects. 3 Erythromycin kinetics were adequately described by a classical two compartment open model with little intersubject variability. 4 Dose‐related variability occurred. Clearance was independent of dose but T1/2 beta and Vdss increased with dose. 5 Data are presented to show that non‐invasive sampling of urine and saliva are of limited value in studying erythromycin pharmacokinetics.

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Summary. Elicited, mouse peritoneal exudate cells were fractionated by centrifugation on discontinuous Percoll density gradients. TVo subpopulations of neutrophils, each of greater than 90% purity, were isolated at discontinuous density gradient interfaces different from the region of mononuclear ceU enrichment (i.e., 1-0694-1 0871 and 1-0872-1-1002 g/ml for neutrophils and less than 1-0694 g/ml for mononuclear cells). Peritoneal exudate cells were mixed with Proteus mirabitis in the presence of 1% normal mouse serum for 30 min. The mixtures were fractionated on gradients of Percoll diluted with a clacium-free medium. Populations of cells banding at densities greater than 1 -0693 g/ml were washed free of gradient material, and neutrophil suspensions containing intracellular bacteria and which were relatively free of extracellular bacteria were isolated. Less than 7% of the total bacteria present was extracellular. The continuing extracellular presence of a heat-labile component of normal mouse serum was essential for maximal intracellular kill of P. mirabitis by mouse peritoneal neutrophils.

1 Extent and rate of absorption of erythromycin were studied in 24 healthy volunteers whose disposition kinetics after i.v. injections had been previously documented. 2 Two clinically attractive oral dosage regimens were administered: erythromycin stearate tablets 1 h before meals (Regimen A), and erythromycin base capsules 30 min after start of meals (Regimen B), each equivalent to erythromycin 250 mg, 6 h apart for 9 doses. 3 Serum concentrations of erythromycin measured during the 1st and 9th (steady-state) dosing intervals resulted in higher maximum serum concentrations for Regimen A (median 1.1, range 0-3.3 and 2.7, 0.6-7.3 mg/l for Doses 1 and 9, respectively) compared with Regimen B (0.4, 0-2.2 and 1.4, 0.2-4.9 mg/l). 4 Absorption occurred earlier with Regimen A with times to maximum concentrations (median, range) being 128, 60-greater than 360 and 118, 75-210 min for doses 1 and 9 respectively, (lag times 75, 15- greater than 360 and 73, 10-110 min) compared with 303, 130-greater than 360 and 173, 45-greater than 360 min (lag times 183, 70-greater than 360 and 190, 20-330 min) for Regimen B. 5 Where it could be assessed, absolute bioavailability for Regimen A was approximately 30% (Dose 1) and 65% (Dose 9) and 40% for both doses of Regimen B. 6 Whereas individual serum concentration-time curves were accurately predicted by the mean for Regimen A, predictability for Regimen B was impossible due to prolonged and variable lag time. 7 The large intersubject variability in erythromycin serum concentration after oral administration, has been shown conclusively to be related to variability in absorption kinetics and absolute bioavailability rather than to variability in disposition kinetics.