1. The pharmacokinetics, metabolism and partial clearances of codeine to morphine, norcodeine and codeine‐6‐glucuronide after single (30 mg) and chronic (30 mg 8 h for seven doses) administration of codeine were studied in eight subjects (seven extensive and one poor metaboliser of dextromethorphan). Codeine, codeine‐6‐glucuronide, morphine and norcodeine were measured by high performance liquid chromatographic assays. 2. After the single dose, the time to achieve maximum plasma codeine concentrations was 0.97 +/‐ 0.31 h (mean +/‐ s.d.) and for codeine‐6‐glucuronide it was 1.28 +/‐ 0.49 h. The plasma AUC of codeine‐ 6‐glucuronide was 15.8 +/‐ 4.5 times higher than that of codeine. The AUC of codeine in saliva was 3.4 +/‐ 1.1 times higher than that in plasma. The elimination half‐life of codeine was 3.2 +/‐ 0.3 h and that of codeine‐6‐glucuronide was 3.2 +/‐ 0.9 h. 3. The renal clearance of codeine was 183 +/‐ 59 ml min‐1 and was inversely correlated with urine pH (r = 0.81). These data suggest that codeine undergoes filtration at the glomerulus, tubular secretion and passive reabsorption. The renal clearance of codeine‐6‐glucuronide was 55 +/‐ 21 ml min‐1, and was not correlated with urine pH. Its binding to human plasma was less than 10%. These data suggest that codeine‐6‐glucuronide undergoes filtration at the glomerulus and tubular reabsorption. This latter process is unlikely to be passive. 4. After chronic dosing, the pharmacokinetics of codeine and codeine‐6‐glucuronide were not significantly different from the single dose pharmacokinetics. 5. After the single dose, 86.1 +/‐ 11.4% of the dose was recovered in urine, of which 59.8 +/‐ 10.3% was codeine‐6‐glucuronide, 7.1 +/‐ 1.1% was total morphine, 6.9 +/‐ 2.1% was total norcodeine and 11.8 +/‐ 3.9% was unchanged codeine. These recoveries were not significantly different (P greater than 0.05) after chronic administration. 6. After the single dose, the partial clearance to morphine was 137 +/‐ 31 ml min‐1 in the seven extensive metabolisers and 8 ml min‐1 in the poor metaboliser; to norcodeine the values were 103 +/‐ 33 ml min‐1 and 90 ml min‐1; to codeine‐6‐ glucuronide the values were 914 +/‐ 129 ml min‐1 and 971 ml min‐1; and intrinsic clearance was 1568 +/‐ 103 ml min‐1 and 1450 ml min‐1. These values were not significantly (P greater than 0.05) altered by chronic administration.(ABSTRACT TRUNCATED AT 400 WORDS)

1 The pharmacokinetics of pholcodine after two single doses and after chronic administration were studied in healthy human volunteers. 2 Six subjects received single oral doses of 20 and 60 mg of pholcodine according to a balanced cross-over design with an interval of 3 weeks between the two treatments. Blood and saliva samples and all urine were collected over 168 h after each dosage administration. Subsequently, the same subjects received 20 mg pholcodine 8 hourly orally for 10 days. Blood and saliva samples and all urine were collected during an 8 h dosing interval after the last dose on day 11. 3 Plasma, saliva and urine concentrations of pholcodine were determined by a high performance liquid chromatographic assay.4 After the single doses, pholcodine was absorbed rapidly (tmax = 1.6 ± 1.2 h) and eliminated slowly with a mean half-life of 50.1 ± 4.1 h. The renal clearance of pholcodine was 137 ± 34 ml min' and was inversely correlated with urine pH (r = 0.60) but not with urine flow rate. 26.2 ± 3.3% of the dose was excreted as unchanged pholcodine after both doses. The concentration of pholcodine in saliva was 3.6 times higher than in plasma. 5 After chronic administration, the pharmacokinetics of pholcodine were not statistically different from the single dose parameters. 6 Pholcodine did not appear to undergo conjugation. The plasma protein binding was 23.5%. Morphine, in unconjugated or conjugated form, was not detected in the urine of any subject after pholcodine administration.

Hydraulic fracturing is applied for the preconditioning of orebodies prior to cave mining. A major project at Northparkes Mines was carried out in 2006 to investigate hydraulic fracture interaction with shear zones in the E48 orebody. The fracture growth was remotely monitored by tiltmeter and microseismic arrays. The mined fractures were then physically mapped and their geometry was compared to that inferred from the remote monitoring. The fractures were found to be subhorizontal, which was consistent with the tiltmeter and in situ stress data. Shear zones, natural fractures, and veins were crossed by the hydraulic fractures, sometimes producing an offset or step in the fracture path at the crossing site. One hydraulic fracture terminated at a shear zone in close proximity to a lithological contact that may be a stress change boundary. Numerical modelling of hydraulic fracture growth with offsets reveals that such fractures require a higher pressure to propagate and grow more slowly than a straight fracture. Results from numerical modelling indicated that the E48 caveability would prove problematic. The E48 orebody was, therefore, preconditioned using hydraulic fracturing and the footprint of the cave was enlarged. PreconditioningMethods to introduce new fractures to weaken the rock mass and enhance its caveability are needed, particularly if less fractured, stronger orebodies, some with smaller footprints, are to be reliably mined by

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