Pyridostigmine Pharmacokinetic Data

Appendix A

Pyridostigmine Pharmacokinetic Data

Table A.1
Pyridostigmine Pharmacokinetic Data

Characteristic Value Species Source

Onset of action after oral administration 30-45 min Human McEnvoy, 1991

Onset (time to initial detection in blood) 30 min Human Whinnery, 1984

Duration of action after oral administration 3-6 hr Human McEnvoy, 1991

Intravenous elimination half-life 30 min Human ("clinical results") Lietman, 1993

97 min Human Breyer-Pfaff, 1985

1.9 hrs Sidell, 1990, based on Cronnelly, 1980; Breyer-Pfaff, 1985; Kornhauser, 1988

Oral elimination half-life 200 min Human Breyer-Pfaff, 1985

3.7±1.0 hours Human Sidell, 1990, based on Cronnelly, 1980; Breyer-Pfaff, 1985; Kornhauser, 1988

1.78±0.24 hr Human Whinnery, 1984, citing Eur J Clin Pharm, 423-428, 1980

Bioavailability 7.6±2.4% 14% 29% Human Human Human Whinnery, 1984 Breyer-Pfaff, 1985 Kornhauser, 1988

Mean concentration at which 50% of the red blood cell AChE activity was inhibited (IC50) 31.8 ng/ml Human Lietman, 1993

Characteristic Value Species Source

Time to peak plasma concentration, fasting 1.7 hr Human Whinnery, 1984

Time to peak plasma level after oral dosing 1.5-2.5 hrs Human? Kolka, 1991, citing Aquilonius 1980

Time to peak plasma concentration, with food 3.2 hr Human Whinnery, 1984

Plasma clearance 44.62L/hr or 744 ml/min Human Lietman, 1993

0.66±0.22 l/kg^ahr Human Whinnery, 1984

Time at which 95% of the drug is eliminated 8-10 hours Human Kolka, 1991, citing Aquilonius 1980

Total clearance 8.5 (SD 8.7) (ml/min/kg) Human Sidell, 1990, based on Cronnelly, 1980; Breyer-Pfaff, 1985; Kornhauser, 1988

Volume of distribution 1.1 (SD 0.3) L/kg Human Sidell, 1990, based on Cronnelly, 1980; Breyer-Pfaff, 1985; Kornhauser, 1988

Mean rate constant of elimination 1.365/hr Human Lietman, 1993

Urinary excretion 80-90% (SD 0.3) Sidell, 1990, based on Cronnelly, 1980; Breyer-Pfaff, 1985; Kornhauser, 1988

^aWhinnery: from 5 males given 120 mg PB orally.

Table A.2
Animal Data

Characteristic	Value	Species	Source
Urinary Excretion	90%	rat	Yamamoto, Sawada, et al., 1995
Metabolite, 3-hydroxy-N-methylpyridium, as fraction of excreted dose	1/3	rat	Yamamoto, Sawada, et al., 1995
Plasma elimination half life (iv)	19 min	rat	Yamamoto, Sawada, et al., 1995

Additional information derived from rats:

No dose dependence in pharmacokinetic behavior in the range of 0.5-2 µmol/kg of PB in rats (Yamamoto, Sawada, et al., 1995).
Elimination: role of liver and kidneys. Contrary to rapid elimination, high accumulations are found in liver and kidney. Tissue: plasma partition coefficients (Kp) of cholinesterase inhibitors are about eight for liver and 15 for kidney at 20 minutes, suggesting these must be concentratively uphill transported into these tissues like other quaternary ammonium compounds. Though about 50 percent of the dose is distributed into liver and kidney at 20 minutes after intravenous administration, distribution volumes at steady state are relatively small--0.3-0.7 l/kg--larger than the extracellular space and similar to the muscle/plasma concentration ratio. Once in the liver and kidney, PB may not be able to return to plasma compartment; uptake to these tissues may be regarded as an elimination process, and uptake to liver and kidneys may be the major determinant of total body clearance (Yamamoto, Sawada, et al., 1995).

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