Core18: Linear and non-linear pharmacokinetics

線形・非線形薬物動態

📉 High-yield / 要点：Linear PK = dose ↑ → concentration/AUC proportional and CL/T1/2 are constant. Non-linear PK = saturable process → small dose increase can cause large concentration/AUC increase → overdose risk.

Linear kinetics / 線形薬物動態

Occurs when elimination or absorption is non-saturable, e.g. diffusion or filtration.
Also behaves linearly if the process is not near saturation in the relevant concentration range.
Elimination rate is proportional to concentration.
Typical first-order curve:
- Concentration-time curve is negative exponential.
- On a log concentration-time plot, it becomes approximately linear.
In linear kinetics:
- Clearance / CL is concentration-independent.
- Half-life / T1/2 is concentration-independent.
- AUC is proportional to the amount of drug reaching systemic circulation.
- At repeated/constant dosing, steady-state concentration is proportional to dosing rate.

Non-linear kinetics / 非線形薬物動態

Occurs when elimination or absorption becomes saturable.
If concentration exceeds Km, the process loses proportionality.
Elimination becomes slower than expected and may approach a maximum rate.
In non-linear kinetics:
- Relevant CL and T1/2 cannot be reliably fixed.
- AUC can increase disproportionately, e.g. 2× dose → ~4× AUC.
- Repeated dosing may cause unexpectedly high steady-state concentration.
- Monitoring is often needed for dose titration.

Examples / 例

Ethanol：non-linear over the relevant clinical range.
Phenytoin：saturable elimination; narrow safety margin.
Voriconazole：non-linear at higher doses.
Methotrexate：non-linear absorption may require route adjustment.

Clinical meaning / 臨床的意義

Feature	Linear PK	Non-linear PK
Dose vs concentration	Proportional	Disproportionate
Clearance	Constant	Not fixed
Half-life	Constant	Not fixed
Overdose risk after dose increase	Predictable	High

Remember / 覚え方

Linear = predictable
Non-linear = saturated + dangerous
Phenytoin: small dose change can cause big level change