Table 4.
Pharmacokinetic and pharmacodynamic properties of lead spectinamides.
| Property | Measurement | 1329 | 1443 | 1445 | 1544 | 1599 | Spectinomycin (unless noted) |
|---|---|---|---|---|---|---|---|
| Protein serum binding (Rat) | % bound | 28.6 (8.9) | 13.1 (0.3) | 27.7 (4.3) | 15.0 (9.9) | 12.5 (1.7) | 12.7 (7.5)2 |
| Microsomal metabolic stability (Rat) | % remaining after 90 min incubation | 83.7 (16.4) | 109 (2.7) | 102 (1.2) | 67.3 (16.3) | 88.0 (4.2) | 80.4 (19.9) |
| IV Pharmacokinetics (Rat) | t½ (h)1 | 0.52 (6.8) | 0.44 (0.8) | 0.45 (7.7) | 1.06 (9.2) | 0.58 (20.8) | 0.75 (49.3)2 |
| Vd (L/kg) | 1.15 (11.9) | 0.46 (10.3) | 0.57 (7.7) | 0.87 (22.9) | 0.82 (34.5) | 0.76 (45.2)2 | |
| CL (L/h/kg) | 0.72 (10.8) | 0.89 (6.8) | 0.56 (8.9) | 0.94 (6.3) | 1.22 (14.3) | 0.60 (11.5)2 | |
| % excreted unchanged in urine | 45.6 (9.7) | 86.9 (12.5) | 108 (8.3) | 51.8 (9.9) | 88.5 (11.5) | 55.3 (27.0)2 | |
| Postantibiotic effect | at 10 × MIC (h) | 18.8 (7.9) | 26.9 (48.9) | 15.7 (22.5) | 75.4 (38.4) | 133 (19.6) | Strep 132 |
Values represent means (% coefficient of variation).
Abbreviations: t½: half life; Vd: volume of distribution; CL: clearance; Strep: streptomycin. All lead spectinamides had excellent aqueous solubility >1mM.
1
t½ is based on decline of plasma concentration in the therapeutically relevant concentration range.
2
Indicates values published in reference number45 and included for comparison.