Chapter 6 Basic Pharmacokinetics

Chapter 6 今日のメモ☆
今回の項は苦手だったPharmacokinetics（薬物動態学）の内容。
計算式も多く、数学の苦手な自分は積分の式が出てくるだけで拒否反応が出てしまうけど、こんなに何回もやることになるのであれば、前の段階でしっかり理解しておけばよかった…と後悔。何回もやっているうちに理解は深まってきたので、青本でおさらいしながら計算式を復習。

Zero-order reaction（0次反応）
 dC/dt = -k0
 C = -k0t + C0
 t1/2 = C0/2k0 (半減期は初濃度に比例）

First-order reaction（1次反応）
 dC/dt = -kC
 C = C0e*-kt　(lnC = -kt + lnC0, logC = -kt/2.303 + logC0)
 t1/2 = ln2(=0.693)/k (半減期は濃度に無関係で一定）

Second-order reaction（2次反応）
 dC/dt = -k*C2
 C = -k0t + C0
 t1/2 = 1/kC0 (半減期は初濃度に反比例）

One-compartment model
 apparent volume of distribution: Vd = D/Co
 Total body clearance: CLtot = F*Do/AUC   CLtot = CLr + CLh  CLtot = Vd*k
  ※CLr = CLtot * 腎排泄率, CLh = CLtot * 肝代謝率　
  ※CLh = Liver blood flow: Q*　extraction ratio: Eh

 k = 代謝速度定数(km)+尿中排泄速度定数(ku)
  ※km = k*肝臓で代謝を受けた割合, ku = k*腎臓で未変化たいとして排泄された割合

 CLr = ku * Vd
  Clearance rate < 1.0 : filtration + reabsorption
  Clearance rate = 1.0 : filteration only
  Clearance rate > 1.0 : filteration + active tubular secretion
   - Glomerular filtration（糸球体濾過）: creatinine&inulin are used to measure the GFR
   - Tubular reabsorption（尿細管再吸収）
   - Active tubular secretion（尿細管分泌）：carrier-mediated active transport

 Steady-state condition（定常状態）
  : the fraction of drug absorbed equals the fraction of drug eliminated from the body
  D/τ = Css * CLtot　(D/τ = Css * Vd*k)
   ※C≒90%：t1/2*3.32,　C≒95%：t1/2*4.32, C≒99%：t1/2*6.65
   ※τ = t1/2　のとき、Cmax= 2*Cmin

  Loading dose: DL = Css*Vd (t1/2 = τのとき DL = 2*Css)

Two-compartment models
 Districution phase & Elimination phase
  Michaelis-Menten kinetics
   dCp/dt = Vmax * Cp/Km +C
    ※Vmax/2 = Km

 Nonlinear pharmacokinetics
  - AUC, excrete in the urine is not proportional to the dose
  - t1/2 ↑　CLtot↓

Noncompartment methods
 Mean Residence Time(MRT:平均滞留時間) = AUMC/AUC
  IV: MRT = 1/k
  PO: MRT = 1/ka + 1/k

Today's question
- multiple-dose regimens(多剤投与)の問題
Q: The principle of superposition in designing multiple-dose regimens assumes that
(A) each dose affects the next subsequent dose, causing nonlinear elimination.
(B) each dose of drug is eliminated by zero-order elimination.
(C) steady-state plasma drug concentrations are reached at approximately 10 half-lives
(D) early doses of drug do not affect subsequent doses.
(E) the fraction of drug absorbed is equal to the fraction of drug eliminated.

A: (D)When a multiple-dose regimen is calculated, the superposision principle assumes that previous drug doses have no effect on subsequent doses.  Thus, the predicted plasma drug concentration is the total plasma drug concentration obtained by adding the residual drug concentrations found after each previous dose.